Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1)

R. Eberle; L. Jones-Engel

doi:10.1155/2018/5248420

Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1)

Eberle, R.;Jones-Engel, L. 2018-02-13 00:00:00 Hindawi Advances in Virology Volume 2018, Article ID 5248420, 17 pages https://doi.org/10.1155/2018/5248420 Review Article Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1) 1 2 R. Eberle and L. Jones-Engel Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater,OK74078,USA Department of Anthropology and Center for Studies in Ecology and Demography, University of Washington, Seattle, WA 98195, USA Correspondence should be addressed to R. Eberle; r.eberle@okstate.edu Received 10 October 2017; Accepted 10 January 2018; Published 13 February 2018 Academic Editor: Anuj Sharma Copyright © 2018 R. Eberle and L. Jones-Engel. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Monkey B virus (Macacine alphaherpesvirus 1; BV) occurs naturally in macaques of the genus Macaca, which includes rhesus and long-tailed (cynomolgus) monkeys that are widely used in biomedical research. BV is closely related to the human herpes simplex viruses (HSV), and BV infections in its natural macaque host are quite similar to HSV infections in humans. Zoonotic BV is extremely rare, having been diagnosed in only a handful of North American facilities with the last documented case occurring in 1998. However, BV is notorious for its neurovirulence since zoonotic infections are serious, usually involving the central nervous system, and are frequently fatal. Little is known about factors underlying the extreme neurovirulence of BV in humans. Here we review what is actually known about the molecular biology of BV and viral factors aec ff ting its neurovirulence. Based on what is known about related herpesviruses, areas for future research that may elucidate mechanisms underlying the neurovirulence of this intriguing virus are also reviewed. 1. Introduction zoonotic BV infection following exposure to macaques has a mortality rate of∼80%. Here we review what is known about Herpesviruses are ubiquitous viruses, found in a wide variety this relatively neglected virus with regard to its infamous of species including mammals, birds, and reptiles. Three neurovirulence. subfamilies of the Herpesviridae family (Alpha-, Beta- and Gammaherpesvirinae) are found in the order Primates. Of 2. BV in Its Natural Host these, alphaherpesviruses typically infect and remain within theperipheralsensorynervoussystemforthelifeoftheirhost Monkey B virus (BV) occurs naturally in all 17 species as part of their natural life cycle. The close and prolonged of macaque monkeys that comprise the genus Macaca. association of these viruses with their host over its entire Macaques are ecologically adaptable monkeys and are the lifetime with only rare impairment of nervous system func- most numerous and widely distributed nonhuman primate tion implies an exquisite degree of host-virus coadaptation. ontheplanet.em Th ajorityofmacaquespeciesaredistributed On occasion stability of this commensal symbiotic host-virus throughout Asia and their ubiquity has led to three of these relationship can be altered, resulting in severe or even fatal species (M. mulatta, M. fascicularis, and M. nemestrina)being diseaseoeft ninvolving thecentral nervoussystem(CNS). used as biomedical research models for nearly a century [1– In cases where an alphaherpesvirus infects a host of another 4]. Although known by several names over the years since species, the result can be, but is not always, catastrophic. eTh its initial isolation in 1932 (Herpesvirus simiae, monkey B most notorious example of this is monkey B virus (Macacine virus, Herpes B, and Cercopithecine herpesvirus 1), BV is alphaherpesvirus 1; BV), an alphaherpesvirus enzootic in currently designated as Macacine alphaherpesvirus 1bythe macaques of the genus Macaca.Though exceptionallyrare, International Committee on Taxonomy of Viruses. 2 Advances in Virology From a biological standpoint, in macaques BV is very 3. Zoonotic BV Infection much like herpes simplex virus (HSV) in humans. Both In 1932 a young physician, William Brebner, performing HSV and BV are normally transmitted horizontally via direct poliovirus research with rhesus macaques was bitten on the contact and exchange of bodily secretions [3, 5–7]. eTh finger [40–42]. He developed herpetic-like lesions on the prevalence of BV in macaques is related to age, increasing finger, and the infection eventually progressed to involve the progressively from infant to adult [8–17]. eTh re are very CNS. The patient died several weeks later from an acute few studies on the prevalence or transmission of BV in ascending myeloencephalitis. A herpesvirus was isolated free-ranging populations. In captive macaque colonies, very from several tissues at autopsy. Although initially identified young monkeys (<2 yr of age) usually acquire BV as an as HSV, the virus was subsequently shown to be distinct from oral infection, while in socially and reproductively mature HSV and was designated as “the B virus” [40, 42]. macaques primary BV infections are usually genital. eTh While the exact number is not available, less than 60 prevalence of BV in adults of both wild populations and additional cases of pathogenic zoonotic BV infection have captive breeding colonies typically ranges from 70% to nearly occurred sporadically over the last 85 years, all resulting 100%. Only rarely does BV cause lethal infections in healthy from exposure to laboratory or captive macaques or macaque macaques, just as HSV rarely causes encephalitis or other tissues [2,4,5,43–50]. WhilezoonoticBVinfectionsare serious disease in humans [18]. exceedingly rare, the fatality rate is 70–80% and many survivors are left with deteriorative neurologic sequelae. eTh As with HSV in humans, most primary BV infections majority of exposures have been associated with bites or occur in mucosal epithelium and do not usually produce scratches from captive, laboratory-housed macaques. How- overt clinical signs, although lesions are sometimes visible ever, additional modes of exposure have been implicated on close inspection [27]. As the virus replicates in epithelial including mucosal membrane contact with macaque urine cells, sufficient levels of infectious virus accumulate allowing and/or feces, needlestick injury, and contamination of cuts the virus to invade unmyelinated sensory nerve endings with material from primary macaque cells in the labora- present in the epidermis. Once in sensory neurons, the tory [43, 44, 48]. With the sole exception of one spousal virus establishes a latent infection in the sensory ganglion, person-to-person infection [47], all zoonotic BV infections where the viral genome is retained in the nuclei of neurons have involved primate veterinarians, animal care personnel, without entering the lytic viral replicative cycle that occurs in or laboratory researchers in North America working with epithelial cells [6, 28–30]. Viral replication in epithelial tissue macaques or macaque biologics. BV is the single most serious is eventually controlled and the virus is eliminated by the occupational zoonotic concern for persons working with or host adaptive immune response. eTh only indication that a around macaques. monkey continues to harbor BV is the presence of circulating While the clinical course of zoonotic BV infections can antiviralIgG.Ithasbeen shownincaptive macaquesthat,in vary,initial symptomsusuallydevelop within1–3weeks ofan rare instances, usually in infants or the very young, primary exposure incident [51]. The nature of initial clinical symptoms infections may not end with the establishment of latency, also varies but usually includes nonspecific u-li fl ke symp- but rather progress as generalized infections that spread toms, vesicular herpetic lesions at the site of exposure, and throughout the body and are frequently fatal [31–34]. symptoms indicative of involvement of the peripheral and/or As is typical of other alphaherpesviruses, BV can period- central nervous systems. The infection progressively spreads ically reactivate from the latent state in response to various along sensory nerves into the spinal cord and ascends into the stressful stimuli, resulting in shedding of infectious virus. brainstem. Typically, the destruction of nervous tissue as the While lesions may be apparent, most recurrences do not virus spreads within the CNS results in encephalomyelitis and produce clinically apparent lesions; rather, infectious virus is respiratory failure in terminal stages of the infection. Once theCNS isinvolved,thefinaloutcomeisalmostinvariably shed asymptomatically. Like HSV in humans, the frequency death. of BV shedding appears to be fairly low (2-3%) [35–37]. Stress related to social/housing challenges, transportation, oTh ughmostpersonsknowntobeinfectedwithBVdie, immunosuppression, and seasonal breeding have all been some do survive and some survivors can periodically shed linked to reactivation of latent BV [6, 7, 38, 39]. virusaeft rrecovery[46,52–54].Severalcases of zoonotic BV have also occurred in persons who have a history of In many ways, BV is the macaque equivalent of human working with macaques but without any known BV exposure HSV: BV and its macaque hosts have coevolved, resulting immediately prior to the appearance of clinical signs. Both in an exquisitely fine-tuned interaction with one another of these observations suggest that BV latency not only that results in perpetuation of the virus within the host’s occurs in humans, but that reactivation of latent BV can be nervous system with minimal adverse eeff cts on the host but associated with clinical disease [47, 54, 55]. Since primary also with occasional shedding of infectious virus that can be BV and HSV infections in the natural host species are usually transmitted to a na¨ıve host, thereby ensuring perpetuation asymptomatic, the potential exists for asymptomatic zoonotic of the virus. eTh notorious neurovirulence of BV is therefore BV infections to occur as well. However, there has only been not evident in its natural macaque hosts; the neurovirulence one study that tested persons working with captive macaques of BV only becomes apparent when BV infects other species, for serological evidence of BV infection [56]. None were particularly humans. Advances in Virology 3 detected, suggesting that asymptomatic infections are likely macaque contact and injury [19]. If such persons had experi- uncommon, if they do occur. enced BV infection over their years in close contact with wild macaques, their antiviral serum antibodies should differ in A puzzling aspect of zoonotic BV infections is the notable their virus-specificity from that of persons never exposed to lack of any fatal or even clinically evident BV infections in BV. When an HSV infected person is infected with an anti- Asia where BV-positive macaques and humans have copious genically related virus, an anamnestic response will occur to close interactions, and exposure to macaque bodily uids fl antigens shared by the two viruses, while a de novo response through bites, scratches, and mucosal splashes is common [11, will occur to antigens specific to the second virus. us, Th 19, 57–59]. The human-macaque interface is diverse and deep detection of BV-specific antibodies is a difficult problem, in Asia, in part because of cultural and religious beliefs that astheBV-specica fi ntibodyresponsedevelopsmoreslowly provide a context for tolerance and a measure of protection andmaybe overshadowed by theimmediateandstrong for these ubiquitous monkeys. Macaques, particularly the response to cross-reactive antigens. Consequently, persons abundant rhesus, long-tailed and pigtail monkeys, are found infected with HSV who had experienced an asymptomatic at the thousands of temples and shrines located throughout BV infection would be expected to have higher levels of a broad geographic swath extending east from Afghanistan antibodies directed against antigens shared by all primate to Japan and south through the Indonesian archipelago. alphaherpesviruses than would be present in sera of persons Millions ofpeople wholiveandwork atthesesites,aswell only infected with HSV. as those who worship, have frequent contact with macaques. Additionally, many of these sacred sites are also international Limited testing compared the relative reactivity of sera tourist destinations, drawing hundreds of thousands of vis- from persons working in monkey forests with that of persons itors each year who come to appreciate the culture and to having no known contact with monkeys (negative controls) feed and interact with the monkeys. Human exposures are and patients that died of zoonotic BV infection (positive routine, with macaques aggressively pursuing food handouts controls) (Figure 1). When sera were tested by ELISA against whileclimbingonvisitors. Bitesand scratchescommonly HSV and multiple simian virus antigens, it was evident occur, especially to international tourists who lack experience that a few monkey forest workers had higher levels of with monkeys, when humans either fail to relinquish food reactivity with simian virus antigens than was evident in or behave in a manner the monkeys deem threatening. In most other monkey forest workers or negative control sera a retrospective study of French tourists seeking medical (Figure 1(a)). Such elevated antibody levels directed against treatment for an animal bite received in Southeast Asia, cross-reactive alphaherpesvirus antigens suggests that these most reportedthattheinjuringanimalwas amonkey[60]. individuals have experienced an infection with a virus anti- Studies have shown that between 6 and 40% of visitors to a genically related to but different from HSV. Further analysis monkey temple will be bitten, and thus it is not surprising that by sensitive competition ELISA [23, 24] conrm fi ed that the zoonotic transmission of a primate retrovirus (simian foamy reactivity of these sera was consistent with that of having virus) has been documented following exposure to macaques been infected with BV (Figure 1(b)). Given the absence of any in Asia [20, 61–63]. history consistent with typical BV infection (i.e., infections with neurological involvement), it is possible that these In addition to the hundreds of monkey temples across persons experienced asymptomatic BV infections. However, Asia, tens of thousands of macaques are free-ranging in urban if asymptomatic BV infections do occur in Asia, then the lack areas such as Singapore, Hong Kong, Delhi, and the famous of apparent asymptomatic BV infections in the US presents a wild monkey parks of Japan. Macaques are also commonly different enigma. found as pets, and a centuries-old tradition of keeping and When assessing the neurovirulence of BV, it is important training performing monkeys continues in China and Japan. Finally, it should be noted that Indonesia, Thailand, Malaysia, to recognize that, within Asia where hundreds of thousands Singapore, Vietnam, Cambodia, Laos, Philippines, China, of macaques come into daily contact with millions of peo- and Japan all have active biomedical research programs ple, there is no conclusive evidence of zoonotic infections, and/or primate breeding research centers which collectively neurological or otherwise. Genetic differences in human employ thousands of workers and involve tens of thousands subjects (Asian versus non-Asian background) would seem of macaques each year. Many of these breeding facilities an unlikely explanation for the lack of fatal BV infections in operate under conditions of extreme animal overcrowding Asia since many non-Asian tourists visiting monkey forests with husbandry and handling protocols that are substan- in Asia and non-Asian military troops serving in Asia have dard (Jones-Engel, pers. observ.). Despite frequent contact experienced bites and scratches from macaques without any between humans and free-ranging, temple, pet, or urban resulting zoonotic BV infections [11, 19, 61, 64]. Similarly, macaques in Asia, fatal cases of BV have only occurred in inaccurate diagnosis of zoonotic BV infections in rural areas the US and Canada following contact with captive macaques. with limited healthcare seems unlikely explanation as tens of This geographic restriction of zoonotic BV infections has long thousands of macaques are free-ranging in large metropolitan been and remains a puzzle. areas in Asia where access to healthcare, diagnostics, and case One immediate question is whether or not BV is even follow-up are readily available (e.g., Singapore, Hong Kong, zoonotically transmitted in Asia. There is no question that and Kyoto). It is even less likely that clinicians in a tourist’s individuals in communities living near macaques or who home country would fail to diagnose BV when presented work in SE Asian monkey forests have a history of extensive with a history of a macaque bite and neurological symptoms. 4 Advances in Virology 1.0 100 0.9 0.8 Normal Macaque Normal human 0.7 (HSV−/BV+) (HSV+/BV−) 0.6 0.5 0.4 0.3 Fatal BV #1 0.2 Fatal BV #2 (HSV+/BV+) (HSV+/BV+) 0.1 0.0 Normal human HSV+ Fatal Monkey temple workers Monkeys BV Temple worker Temple worker HAD43 60 BH9 1 2 3 4 56 7 12 34 567 log competing antigen dilution (a) (b) Figure 1: Evidence of possible asymptomatic BV infections in Asia. (a) Sera from individuals working at monkey forests in SE Asia [19, 20] were tested by ELISA as described [21, 22] against HSV1 (dark blue), HSV2 (light blue), BV (red), HVP2 (orange), squirrel monkey herpesvirus (light green), and spider monkey herpesvirus (dark green) antigens. HSV1 OD values were normalized to 1.0 to assess relative levels of reactivity with cross-reactive antigens. Average levels of cross-reactivity with BV and HVP2 in normal HSV-positive control sera (individuals with no known contact with monkeys) are indicated by the dashed line, and average levels of cross-reactivity with the two S. American monkey viruses are indicated by the dotted line. The four sera from monkey forest workers and serum from a fatal case of zoonotic BV infection have higher levels of cross-reactivity with all simian virus antigens than do control sera. (b) Competition ELISAs were performed as described [23, 24] to determine if sera from monkey forest workers with high levels of cross-reactivity were consistent with having been infected with BV. Soluble antigens (extracts of cells infected with HSV1 (blue), BV (red), or uninfected cells (black)) were used to compete the binding of serum to HSV1 antigen coated onto the ELISA plates. Binding of control HSV1-positive serum was inhibited only by soluble HSV1 antigen, not by BV or control antigens. Binding of BV-positive macaque serum (HSV-negative) to the solid phase HSV1 antigen was equally competed by soluble HSV1 and BV antigens. Binding of sera from two patients that died of zoonotic BV infection (both HSV1-positive) were competed by both HSV1 and BV soluble antigens, although competition by BV antigen was less than by HSV1 antigen. Binding competition forserafromtwomonkeyforestworkers(bothHSV1-positive)wassimilartothatofzoonoticBVpatient sera. Despite being exposed to populations of macaques known to have operated in Asia for decades, some of which contain be BV positive, no cases of zoonotic BV have been reported up to 10,000 macaques, there have been no reported cases among international tourists [65]. of zoonotic BV. eTh macaques housed in these facilities Perhaps a more likely explanation lies in the monkeys, are exported and are a source of animals used in biomed- that is, captive versus free-ranging. Do captive macaques ical research in North America. Other possibilities such as shed BV more frequently as a result of some husbandry recombinant BV in captive monkeys that arose through past practices? When they are shedding do they shed more virus? practices of cohousing of different species during capture and Do free-ranging monkeys preferentially shed virus (or more shipping have also been raised. eTh lack of BV isolates from virus) genitally rather than orally, while captive monkeys shed free-ranging macaques for comparison to BV isolates from more orally? All these are questions that have been examined captive macaques and isolates recovered from zoonotic cases only supercfi ially or not at all. It is particularly intriguing will be necessary to address these and many other aspects of that amongst the dozens of primate breeding facilities that BV neurovirulence. Normalized OD value HSV1+ HSV1+ HSV1+ HSV1+ HSV2+ HSV1+ HSV2+ HSV1+ BV+ Baboon Sq Monkey HAD43 HAD20 HAD48 HAD53 % inhibition of test serum binding Advances in Virology 5 4. Model Systems for Zoonotic BV Infection of a lethal neurological infection in a black-and-white colobus monkey (Colobus guereza) [81]. Given the lower biosafety Rabbits have historically been used as an animal model for rating of HVP2 (BSL2 versus BSL4 for BV), HVP2 is an BV infections. Until recently, all testing of antivirals for anti- attractive model for BV cross-species infections [74, 76]. BV activity was conducted using rabbits [66–70]. Rabbits are however not an ideal model system given their size, the 5. Molecular Aspects of BV relative paucity of immunological reagents, and the difficulty of housing and handling infected animals under stringent From the time of its original isolation in 1932, extensive biohazard conditions. Infant mice were found to be suscepti- antigenic cross-reactivity between BV and HSV has been ble to BV and using this model, the spread of BV in an axonal- noted, indicating that these viruses are closely related [42, 82– transsynaptic manner was demonstrated [71, 72]. However, 85]. Subsequent studies revealed that alphaherpesviruses of this model has a number of inherent drawbacks (immature baboons (HVP2), vervets (SA8), and chimpanzees (ChHV) immune system, size, and dependable numbers/availability) and to a lesser extent the viruses of squirrel monkeys (HVS1) and has not been used further. Infection of young adult andspider monkeys(HVA1)areallclosely related[23,83, 85– mice by intramuscular (i.m.) injection (similar to a bite 90]. Phylogenetic analyses of the alphaherpesviruses based on wound) found substantial variation in the neurovirulence of gene sequences have defined three major clades of primate various strains of BV isolated from rhesus monkeys, but this alphaherpesviruses consisting of the hominid viruses (HSV1, model system was not highly reproducible [73]. However, HSV2, and ChHV), cercopithecine (African and Asian) inoculation of young adult Balb/c mice by skin scarification monkey viruses (BV, HVP2, and SA8), and the platyrrhine (S. of the flank was found to produce disease very similar to American) monkey viruses (HVS1 and HVA1) [91–93]. Based that seen in humans and to be very reproducible [74]. This on the close relatedness of BV and HSV, the relative lack of mouse model has recently been used for testing ecffi acy of research on the simian viruses, and the biohazard concerns in antiviral drugs and molecular studies on BV [75–77]. Lesions working with infectious BV, comparatively little experimental in the brainstem of BV infected mice are characterized by molecular work with BV has been published. us, Th most perivascular cuffing with mononuclear cells, discrete foci of of what is “known” about BV structure, protein functions, neuronal necrosis, gliosis, and discrete areas of destruction and viral replication is actually extrapolationed from what is of white matter within reticular tracts, accompanied by large known for HSV. However, as more work is done with BV and foamy macrophages (gitter cells) similar to those present related simian viruses, significant differences between these in spinal cord lesions. Viral antigen is also present within viruses and HSV become more apparent. neurons and glial cells, and the severity of inflammation BV has the typical virion structure of alphaherpesviruses, is related to the amount of viral antigen present [73]. The the genome being enclosed within an icosahedral capsid inflammatory response to infection has been linked to the that is embedded in an amorphous protein tegument and lethality of HSV encephalitis in mice [78, 79], and an surrounded by a lipid membrane envelope [51, 94]. Like HSV, aggressive inflammatory response in neural tissue may well the lytic replication cycle of BV is rapid with extracellular contribute to the lethality of BV infections in both mice and progeny virus appearing∼6–8 hrs aer ft infection (PI) [95]. humans. And as for HSV, synthesis of BV proteins appears to follow In this mouse model, all BV isolates from rhesus the immediate early/early/late gene expression paradigm. macaques and an isolate from a long-tailed macaque (M. In 1971, an isolate of BV from a rhesus macaque was fascicularis) were found to have similar LD values of adapted to replicate in primary rabbit cells, and this strain approximately 10 PFU [77]. In contrast, isolates from pigtail (E2490) now serves as the “standard” or “laboratory” BV (M. nemestrina) and lion-tailed macaques (M. silenus) were strain [69, 96]. The genome sequence of this strain has not lethal (at 10 PFU) despite producing clinical signs of neu- been determined [97–99]. Recently, genome sequences of rological involvement. This is interesting when one considers a number of additional BV strains from various macaque that most if not all cases of zoonotic BV have been associated species have also been determined [77, 100]. BV genomes with exposure to rhesus or long-tailed macaques rather than range in size from 154,958 to 157,447 bp, the differences being pigtail macaques (lion-tailed macaques are endangered and largely due to variation in the number of iterations of repeated not used in biomedical research). sequence units in specific areas of the genome. eTh BV As mentioned above, the neurovirulence of BV actually genome has a very high G + C content (∼75%) and its genetic relates to its neurovirulence in nonnatural host species. In arrangement is orthologous to that of HSV (Figure 2). Based this regard, it is interesting that no zoonotic infections due to on PCR/sequencing of a small region of the BV genome, the two viruses most closely related to BV, HVP2 of baboons different “genotypes” of BV were identified that correlated (Papio spp.) and SA8 of vervets (Cercopithecus aethiops), with the macaque species the virus was isolated from [24, have been reported (with one probable exception [50]). Both 101, 102]. Comparison of complete genome sequences of baboons and vervets have long been used in biomedical BV isolates from different macaque species confirmed the research and exposure incidents have certainly occurred. It division of BV into host species-based genotypes [77]. While thus appears that when SA8 or HVP2 are transmitted to sequence identity among BV isolates from rhesus macaques humans they both undergo abortive infections. It is thus or between isolates from pigtail macaques is>99%, sequence interesting that most HVP2 isolates have been shown to be identity among different BV genotypes is only ∼89–95%. justasneurovirulentasBVinmice[74,80]andtobethecause Comparing the genome sequences of all BV isolates, most 6 Advances in Virology U U R R R R ‘a’ ’a’ ‘a’ L L S S (a) ∗∗∗ ∗∗∗ ∗∗ ∗ 116 118 120 122 124 126 128 130 132 (b) RL2 (ICP0) RL1 (34.5) RS1 (ICP4) OriS ORF P ORF O LAT RNAs L/ST RNAs Figure 2: Genomic organization of BV. The BV genome is comprised of two unique regions (U and U ) in which open reading frames L S homologous to the UL1–UL56 and US1–US12 genes of HSV are located, respectively (a). eTh U and U regions are each flanked by repeat L S regions (R an R , resp.) with the ‘a’ repeat present at the ends of the genome and between the internal copies of R and R .TheR and R L S L S L S regions are enlarged in (b) to indicate the position of the following features discussed in the text: predicted ORFs (green), HSV ORFs not found in BV (blue), the origin of DNA replication in R (yellow), miRNAs (asterisks), islands of reiterated sequences (magenta), and the region deleted in the E90ΔRL1 mutant (red). coding sequences, miRNAs, and small RNAs are highly structural capsid proteins (which as a functional group are conserved [77, 100, 103, 104]. The most prominent differences the most conserved proteins) and viral enzymes. However, a are located in areas of the long and short repeat regions (R number of BV proteins have regions of dissimilarity relative and R , resp.) of the genome that do not encode proteins, to other simian viruses and even among different genotypes miRNAs, or small RNAs. Within these areas, there are islands of BV. Given the interaction of viral immediate early (IE) of reiterated sequences. While the primary sequence of these proteins with host cell proteins to facilitate expression of the reiterated repeat units and the number of iterations are viral DNA and initiate the lytic replication cycle, it might not conserved among all BV isolates, the positions of these be expected that the IE proteins would be highly conserved. repeat islands are conserved suggesting they likely serve some However, these regulatory IE proteins are actually some of the unknown function. least conserved, both among BV genotypes and between BV The genome of BV (as well as HVP2 and SA8) is very and other primate viruses. By virtue of their expression on the similar to that of HSV2 and ChHV in its genetic organization, surfaceofvirions andinfectedcells,glycoproteins andother with homologs of almost every HSV gene being present in the membrane associated proteins are another group of proteins same order and orientation in BV [77, 92, 99, 105, 106]. er Th e that likely interact with elements of host cells. While some are some minor differences like the grouping of some genes are strongly conserved (>90%AAsequenceidentity), others into different cotranscriptional units [107]. However, there are very poorly conserved (<62% AA identity). Consistent is one major difference, that being the lack of a detectable with this, a number of glycoproteins have some degree of homolog of the RL1 (𝛾34.5) and ORF P genes in the simian virus-specific antigenicity. The gB (UL27) and gD (US6) viruses [92, 99, 105, 106]. This was somewhat unexpected glycoproteins are major immunogens of BV, and while both as both of these genes have been shown to be involved arestructurallyconserved andhavemanycross-reactiveepi- in neurovirulence of HSV (see below). It should be noted topes, each also has some degree of antigenic BV-specificity however that none of the alphaherpesviruses of nonprimate [70,87,108,109,116,117].BoththegG(US4)andgC (UL44) animals have homologs of the RL1 or ORF P genes either. glycoproteins are much less conserved and are largely BV- Based on DNA sequence data, variation in predicted specific antigens with respect to HSV, but still exhibit some amino acid (AA) sequence identity of homologous BV and antigenic cross-reactivity with the homologous glycoproteins HSV2 proteins averages 62.5% [99]. In contrast, average of HVP2 and SA8 [25, 109, 110, 116, 118–120]. Regardless of AA sequence identity values are approximately 95% among the degree of conservation/divergence of BV proteins from BV strains, 87% between BV and HVP2, and 83% between those of other related viruses, with one exception there are BV andSA8[100,105,106]. ThislevelofAAsequence no studies where the involvement of specific BV proteins homology is consistent both with previous studies that in neurovirulence has been examined. The one exception is detected antigenic cross-reactivity of almost all BV proteins the UL41 gene which encodes the virion host shutoff (VHS) with homologous proteins of HSV [83, 87, 108–111] and with protein. Deletion of this ORF does not cause a signicfi ant the extensive antigenic cross-reactivity observed between BV reduction in the LD of BV in mice [75]. While BV encodes homologs of all the various HSV and HSV in ELISA, western blot, and neutralization assays [84–86, 112–115]. proteins mentioned above, little is known about these BV The highly conserved nature of most HSV, ChHV, and proteins regarding functional equivalency to their HSV coun- simian virus proteins argues for the homologous proteins of terparts. BV glycoproteins gC (UL44) and gD (US6) as well each virus having similar functions. Certainly this is true for as VHS (UL41) have been shown to have similar structural Advances in Virology 7 and functional properties to their HSV homologs [75, 117, not lethal in mice). It remains to be seen if UL39 underlies 120–122]. While AA homology suggests that BV proteins neurovirulence of BV in mice as it does in HVP2. function much as their HSV homologs do, the functional The HSV R1 protein is involved in evasion of cell death equivalency of all other BV proteins has not been directly by preventing necroptosis in human but not mouse cells examined. As one example, the BV ICP0 (RL2) homolog [129–131]. In mouse cells, the HSV R1 protein interacts with has the characteristic RING n fi ger domain and many other receptor interacting kinase 1 (RIP1) and RIP3 via their RIP structural motifs of the HSV ICP0 (phosphorylation sites, homotypic interaction motifs (RHIMs) which is also present USP7/ND10 localization region, nuclear localization signal, in the N-terminal region of HSV R1, and this interaction and multiple SIM-like sequences [123]). While this certainly ultimately leads to formation of necrosomes and death of indicates that the BV ICP0 protein is structurally very similar the infected cell. In human cells, R1 disrupts the interaction to the HSV ICP0 protein, the actual functional equivalency between RIP1 and RIP3, also in a RHIM-dependent manner, of BV ICP0 has yet to be demonstrated. Furthermore, while thereby preventing necroptosis. Both the BV and HVP2 R1 these various structural motifs are evident, even minor proteins contain this RHIM motif, and the sequence in this differences in their primary AA sequence could have an effect smallareaishighlyconserved.Thereishowever onesubtype- on their differential function in epithelial versus neuronal specific AA substitution in the RHIM of HVP2ap/nv R1, but cells or macaque versus human-macaque cells. the AA residue present in nonneurovirulent HVP2ap isolates is thesameasthatpresentinallBVisolatesthatarelethalin Although not examined in BV, the UL39 gene is inter- mice,suggestingthatthisAAmaynotberesponsibleforthe esting with regard to host-specific neurovirulence. Despite HVP2 neurovirulence phenotype. the lack of any clinical differences in its natural baboon host, phylogenetic analyses and testing in mice place HVP2 6. Does BV Have a Functional Homolog of isolates into two distinct subtypes [26, 80, 124]. One subtype the HSV RL1 (𝛾34.5) Neurovirulence Gene? (HVP2ap) produces no clinical signs of infection in mice following infection with as much as 10 PFU but does induce InHSVboththeRL1(𝛾34.5) gene encoding the ICP34.5 (RL1) an adaptive immune response. In contrast, isolates of the sec- proteinandtheORF Pgene(ontheoppositestrandand ond subtype (HVP2nv) are extremely neurovirulent in mice, overlapping the RL1 gene) have been shown to be primary having an LD of ∼10 PFU (like BV). This dichotomous determinants of neurovirulence in mice [132–137]. Given the mouse-specific neurovirulence phenotype of HVP2 isolates neurovirulent reputation of BV, the finding that BV lacks allowedmappingoftheneurovirulencelocus.Recombi- homologs of both the RL1 and ORF P genes was not expected. nant HVP2ap/nv viruses were constructed and tested for The HSV RL1 coding sequence starts approximately 200 bp neurovirulence in mice. Correlation of the neurovirulence from the internal copy of the ‘a’ repeat (Figure 2). However, phenotype with genome sequence analyses (defining which no ATG initiation codon is apparent within 500 bp of the ‘a’ parts of the genome were derived from HVP2ap versus repeat in any BV strain (or in HVP2 or SA8). Similarly, no HVP2nv) identified a limited region of 3-4 genes that was potential termination codon is present in any of the simian associated with the neurovirulence phenotype. Based on viruses near the initiation point of the L/ST RNAs where this, the UL39 gene was the most likely candidate for the the HSV RL1 termination codon is located. Furthermore, no predicted AA sequence homology exists in the “RL1 region” “neurovirulence gene,” and this was ultimately confirmed by in any of the simian viruses. u Th s, multiple investigators have construction and testing of UL39 ORF-specicfi recombinant been unable to identify a simian virus homolog of the RL1 viruses[125].Thus,replacingtheUL39apcodingsequence or ORF P genes [77, 99, 100, 105, 106]. Despite the lack of with the UL39nv coding sequence makes an HVP2ap virus a discernable simian homolog of the HSV RL1 gene (or an neurovirulent, and vice versa. overlapping ORF P gene on the opposite strand), the RL1 The UL39 gene encodes the large subunit of the ribonu- region between the RL2 start codon and the ‘a’ repeat of cleotide reductase protein (R1). UL39 has been associated the simian virus genomes (1844–2146 bp) is about the same with neurovirulence in HSV (the ability to replicate in size as in HSV and ChHV (2048–2154 bp). This suggests that nondividing nerve cells) and is one of several genes deleted despite the lack of discernable homologs of the RL1 and ORF from prototype HSV gene delivery vectors [126]. While the C- P genes, this region of the simian virus genomes serves some terminal∼75% of the R1 protein is highly conserved and has function. While there are no apparent ORFs in this region of homology to mammalian ribonucleotide reductase proteins, BV,there aretwoislandsofreiteratedsequences,and RNA theN-terminalregionsoftheHSV,HVP2,andBVR1proteins structural analysis of this region (which includes the 5 part are unrelated to other known proteins and (in HSV) are not of the L/ST RNAs) indicates a plethora of potential stem-loop essential for ribonucleotide reductase enzymatic activity [127, secondary structures. The sequence in this region is highly 128].ItisthisN-terminalregionthatisdistinctinthetwo conserved among 15 strains of BV from rhesus macaques HVP2 subtypes, implying that the N-terminal region of the but not between BV isolates from different macaque species. UL39 protein in some way determines the neurovirulence of Whether or not this region encodes functions similar to those HVP2 in mice. Interestingly, this region of BV UL39 exhibits of HSV is not known. similarly extensive sequence variation between BV isolates Comparing the RL1 region sequences of simian virus from rhesus/long-tailed macaques (that are neurovirulent genomes, there are some conserved features. As in HSV2 and in mice) and pigtail/lion-tailed macaque isolates (that are ChHV, the three simian viruses all have three miRNAs, a 8 Advances in Virology BV isolates Mock HSV1 HVP2 E2490 E90-136 12930 20620 24105 32425 Hrs PI: 1 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 Figure 3: Lack of eIF2𝛼 dephosphorylation by BV. Cells were harvested at 1 or 4 hrs PI and western blots were performed with antibody directed against phosphorylated eIF2𝛼 (Cell Signaling Technologies; Danvers, MA) as described [25]. No change in the level of phosphorylated eIF2𝛼 was evident in mock infected cells and the amount of phosphorylated eIF2𝛼 decreased from 1 to 4 hrs PI in HSV1 infected cells. In contrast, phosphorylated eIF2𝛼 levels increased in BV infected cells. potential TATA sequence, and both ICP4 and SP1 binding following infection (Figure 3). Quite the opposite, accumu- site motifs that are likely control elements for transcription of lation of phosphorylated eIF-2𝛼 is readily evident in BV L/ST RNAs [138]. There is also a potential ORF P start codon infected cells. How BV continues to replicate while eIF-2𝛼 is located approximately 760–815 bp 5 of these putative L/ST phosphorylated is not known. transcriptional control elements in all three simian viruses Using the deletion/replacement approach described for (in HSV the ORF P start codon is 3 of the L/ST control other genes [75, 125], a BV mutant (E90ΔRL1) lacking 1162 bp elements). The translated sequence from this start codon in in the RL1 region but retaining 5 transcriptional control BV is conserved only for the initial four codons (M-A-A- elements of the RL2 (ICP0) gene and 2 of 3 miRNAs located R/E), aer ft which no discernable sequence homology exists. adjacent to the ‘a’ repeat was constructed. This mutant Whether this possibly represents an actual start codon to a growsaswellasthe parental wild-typevirus inVero cells, spliced gene or is simply the result of sequence similarity due indicating that this region of the genome is not essential for to the extremely high G + C content of this region (producing BV replication in vitro. When proteins synthesized at various a strong bias towards high-GC codons) is unknown. It times PI were examined (1-2, 4–6, 10–12, and 4–24 hrs PI), may also be that this potentially conserved AA sequence no differences were detectable between the parental wild- is completely irrelevant, conserved DNA sequence instead type virus and the E90ΔRL1 mutant. In primary mouse skin representing part of the conserved transcriptional start site fibroblasts infected at a low multiplicity of infection (MOI; of the L/ST RNAs. 0.3 PFU/cell), wild-type BV forms small plaques by 24 hrs PI HSV mutants lacking the RL1 or ORF P genes are and subsequently spreads to adjacent cells involving the entire attenuated in a number of mouse model systems, and they fail cell monolayer by 48 hrs PI (Figure 4). In contrast, while to spread within the nervous system even when inoculated the E90ΔRL1 mutant also forms small plaques by 24 hrs PI, directly into the brain [132–134, 137]. The ICP34.5 protein these fail to spread with time. Quantitation of infectious playsacrucialroleinallowingHSVtoevadethe host virus produced aeft r low MOI infection reflected this, in innate immune response by blocking MHC II expression that while the E90ΔRL1 mutant does replicate, the amount on the surface of infected cells. When infected, cells ini- of infectious progeny produced at 24 hrs PI is significantly tiateanantiviralinterferonresponsethatprimarily aeff cts less than that produced by wild-type BV. Since Vero cells neighboring uninfected cells making them more resistant to do not produce IFN-𝛽 while primary mouse cells do, this infection, and ICP34.5 deletion mutants are very sensitive suggests that deletion of the RL1 region from the BV genome to this host antiviral IFN-𝛼/𝛽 response [139–141]. Another renders the virus susceptible to the host IFN-𝛽 response. eTh host cell response to infection is activation of double- E90ΔRL1 mutant does however effectively suppress the host stranded RNA-dependent protein kinase (PKR). PKR acts to IFN-𝛽 response when cells are infected with a high MOI, phosphorylate translation initiation factor eIF-2𝛼 resulting in suggesting that low MOI infection with the E90ΔRL1 mutant cessation of protein synthesis in the cell. eTh HSV ICP34.5 allows adjacent uninfected cells to initiate an effective IFN- 𝛽 protein dephosphorylates eIF-2𝛼, thus counteracting eIF- response that the mutant is unable to overcome, preventing 2𝛼 phosphorylation-induced autophagy [142–146]. The C- further spread of the virus. In this respect, the BV RL1 region terminal region of ICP34.5 has homology with GADD34 deletion mutant appears similar to ICP34.5 mutants of HSV. protein which facilitates its interaction with the MyD116 and The E90 ΔRL1 mutant was also tested in mice using the PCNA cell proteins to form a DNA-binding complex [139, skin scarification model to assess what effect this region 146, 147]. ICP34.5 thus appears to be of central importance has on neurovirulence. As mentioned above, HSV mutants to the HSV replicative cycle in many ways. Given the impor- lacking the RL1 gene are not neurovirulent in mice and tance of ICP34.5 functions in HSV, the close relatedness of fail to spread within the nervous system. In contrast, the BV and HSV, and the similar size of the RL1 region of the neurovirulence of the E90ΔRL1 mutant was actually slightly genomes, it is reasonable to hypothesize that this region of increasedrelativetothatoftheparental wild-typevirus,the 3.7 4.4 the genome may serve some similar function(s) in all these mutant having an LD of 10 PFU compared to 10 PFU viruses. However, unlike HSV none of the simian viruses for the parental virus. Even so, the time to death/euthanasia display the ICP34.5 function of eIF-2𝛼 dephosphorylation of infected mice was the same for both viruses (5.5–6 days Advances in Virology 9 24 hrs PI 48 hrs PI E90-136 E90Δ RL1 Figure 4: Deletion of the RL1 region affects BV spread in primary mouse ce lls. Primary murine skin b fi roblast cells were prepared, cultured, and infected as described [26]. At low MOI (0.3 PFU/cell) wild-type BV (E90-136) forms plaques by 24 hr PI and rapidly spreads over the next 24 hrs, while the E90ΔRL1 deletion mutant fails to spread after 24 hrs PI. PI). u Th s, the RL1 region of BV does not appear to encode all allow direct infection of sensory neurons) [148–151]. Second, thesamefunctions ascribedtothe𝛾34.5 protein of HSV and once within a sensory neuron, the linked processes of viral is not a major determinant of BV neurovirulence. replication, establishment of latency, and reactivation from latency could aeff ct the spread of BV within the nervous system. 7. What Else Could Underlie the Extreme Neurovirulence of BV in Replication at the Site of Infection. The occurrence of herpetic Non-Macaque Hosts? lesions at injury sites in zoonotic BV patients suggests that BV can replicate effectively in human epithelial tissue. However, One possibility that has been raised to explain the restriction the rarity of zoonotic BV infections relative to the number of of zoonotic BV cases to North America is that some BV annual exposure incidents that occur and the apparent lack isolates circulating in these captive macaques are potentially or rarity of asymptomatic zoonotic infections could indicate recombinant viruses, the recombinant viruses having arisen that zoonotic transmission of BV does not always lead to an due to past practices of cocaging monkeys of different species active or clinically apparent infection in many or even most during importation. Sequencing of multiple BV isolates from cases. This could be due to any number of things including (1) different US rhesus breeding colonies failed to detect any such monkeys not shedding virus at the time of contact; (2) too low recombinants [77]. However, none of the isolates examined levels of virus transmitted to overcome preexisting (cross- were from zoonotic BV cases. Comparative genome sequenc- reactive) immunity to HSV; or (3) innate host resistance ing of BV isolates from zoonotic cases and from monkeys resulting in inefficient or abortive replication of BV in human could determine if there are specific characteristics (including epithelial cells relative to its ability to replicate in macaque recombinants) that are associated with zoonotic isolates but cells. While it has been shown that HSV replication in rhesus not present in all monkey isolates. In addition, sequencing of cells can be very inefficient or abortive [152–154], such has not BV isolated from free-ranging (noncaptive) monkeys would been shown for BV replication in human cells. A failure of servetoidentifythepresenceofrecombinantvirusesinNorth BV to replicate well in humans at the original site of infection American captive macaques. resulting in insufficient levels of virus to invade sensory In assessing the host-specific nature of BV neuroviru- neurons could result in the majority of exposure incidents lence, differences that occur in how the virus behaves in not leading to active zoonotic BV infections, such cases only the natural versus nonnatural host obviously need to be resulting when high enough levels of infectious virus are examined. There are really two critical points where differ- transmitted to allow infection of sensory neurons without ences in host-virus interactions in humans and macaques need for further amplification of virus by local replication. would most probably aeff ct neurovirulence/clinical disease. Recent studies have begun to investigate the comparative The first is the ability of BV to invade the nervous system. replication of BV in macaque versus human cells. It has been In the normal course of pathogenesis, viral replication in shown that while the HSV gD glycoprotein binds host cell epithelial tissue at the site of inoculation is needed to produce sufficient levels of infectious progeny virus to allow invasion proteins HVEM, nectin 1 and nectin 2 to facilitate viral entry, the BV gD glycoprotein only binds nectin 1 and nectin 2 of sensory neurons innervating the site (this is not necessary if sufficiently high levels of infectious virus are transmitted to in both human and macaque cells [121, 122, 155]. While a 10 Advances in Virology single amino acid mutation was identified in the external repression of the BV genome in human neurons could well domain of gD that aeff cted the stability of binding to nectin result in a very different outcome of infection compared to that seen in macaques. 1, comparison of gD sequences from 19 clinical BV strains isolated from humans and macaques found that this mutation As mentioned previously, there is evidence supporting the ability of BV to establish latent infections in humans and to did not correlate with zoonosis [117], indicating that differing reactivate at later times just as occurs in macaques. Even so, stability of gD binding to nectin 1 is not related to the ability of BV to infect human versus macaque cells. Consistent with slight alterations in the most basic molecular aspects of these processes could have a radical effect on the ultimate outcome this, the gD glycoprotein has been shown to be altogether of BV infections in humans. It may be that in human neurons dispensable for BV entry into both macaque and human cells BV usually overcomes the innate preemptive response of [155]. the neuron to effectively repress viral IE gene expression The HSV IE protein ICP47 (US12) mediates downregu- and establish latency. This would result in lytic replication lation of MHC expression on the surface of infected cells, of BV in human neurons with production of progeny virus thus likely evading activation of host antiviral T cells and and subsequent spread of the virus to other neurons and/or altering susceptibility of infected cells to killing by natural accessory cells. Given the apparently central role played by killer (NK) cells [156]. eTh BV ICP47 protein lacks the TAP- the multifunctional ICP0 protein in the establishment of binding domain of the HSV ICP47 and thus BV fails to latency [123, 161], variant interaction of the BV ICP0 protein downregulate MHC expression in both human and macaque with macaque versus human cell factors could well be a cells, suggesting that the differences in BV and HSV evasion critical factor. of activation of antiviral T cells and susceptibility to NK When reactivated from latency, progeny virions (or virion cells are not responsible for any differential pathogenicity components) are transported anterograde down the axon of BV in humans versus macaques [157]. Similarly, PI3K- where the virus exits the neuron and undergoes lytic repli- dependent Akt phosphorylation (which promotes survival cation in epithelial tissue [148, 162]. While details of how of the infected cell and inhibits apoptosis) is not markedly reactivation from latency occurs are not known, reactivation different in macaque and human b fi roblasts [158]. us, Th there undoubtedly once again involves altered interactions between is no evidence to date to suggest that BV replicates much the latent viral genome and host cell factors aeff cting IE gene differently in human versus macaque epithelial cells. transcription. Since HSV latency associated transcripts (LAT) and both small RNAs and miRNAs appear to be primarily Replication, Latency, and Reactivation in Neurons. Virtually involved in maintaining latency [138, 160], differential expres- nothing is known regarding details of the establishment of sion and/or function of homologous BV RNAs in macaque BV latency or reactivation from latency. However, based on versus human neurons could alter the stability of the latent what is known about HSV, some predictions can be made state in the two species. While some miRNAs and small RNAs aboutwhatmightoccurdieff rentlyintheseaspectsofBV have been identified and mapped in BV [103, 104], nothing is in its natural versus nonnatural host. When HSV infects known about BV LATs or functions of these RNAs. a neuron, the viral envelope fuses with the cell plasma Since reactivation from latency must involve replication membrane, releasing the nucleocapsid and tegument proteins of the virus in the neuron, it has been hypothesized that into the cytoplasm. eTh nucleocapsid (or at least the viral replication and production of progeny virus in neurons is DNA) is transported to the nucleus where the viral DNA much less efficient than in epithelial cells, thereby sparing is immediately coated with histones and cellular repressor widespread destruction of host neurons [163]. This could proteins to prevent viral IE gene expression and entry into well be the case in macaques, but not when BV reactivates the lytic replication cycle, resulting in latency [159, 160]. in human neurons. Instead, BV may replicate much more To counteract this, the viral tegument protein VP16 (UL48) efficiently in human neurons compared to macaque neurons, recruits several host cell proteins to form complexes at IE gene resulting in production of more virus within the nervous promotors that facilitate expression of the viral IE genes and system andmoreecffi ient spread of BV within thehuman progression into the lytic replication cycle [159]. At the same nervous system as seen in fatal zoonotic infections. time, the ICP0 (RL2) IE protein, which is also present in the A similar possibility is that while BV may become latent tegument, degrades host cell proteins involved in repressing in humans, it is reactivated much more readily in humans viral gene expression via its E3 ubiquitin ligase activity. ICP0 than in macaques (days as opposed to months or years). This also competitively binds to certain components of repressor wouldbeconsistentwiththe variabletime (daystoseveral complexes, thus destabilizing the repressor complexes and weeks) between exposure incidents and the first appearance tilting the balance against entry into the lytic replication cycle of clinical symptoms in zoonotic BV patients [5, 46, 51]. In the and favoring latency [123, 161]. This fine balance between natural host, it is likely that only small amounts of infectious lytic replication in neurons and establishment of latency virus are produced in neurons following reactivation from represents an exquisite degree of coadaptation between HSV latency and progeny virions are transported anterograde in anditshumanhost,allowing both tocoexist.Itislikelythat the axon down to the original epithelial site of infection BV follows this same paradigm in macaques, becoming latent where further replication occurs until cleared by an adaptive in sensory neurons with the host adaptive immune response immune response. If reactivation of BV from latency is clearing the initial infection in epithelial tissue. Anything much more efficient in human neurons, it is conceivable that that alters this fine balance between lytic replication and BV could eventually overload the host/virus balance with Advances in Virology 11 successive waves of newly replicated virus infecting many this region of the simian virus genome remains nearly the more neurons than occurs in the natural macaque host. same size as in HSV. Although both the RL1 and ORF P genes Another possibility is that in humans BV is more readily are important determinants of HSV neurovirulence in mice, transported down dendrites than in macaques, resulting deletion of this region of the BV genome has little eeff ct on its in more efficient spread of the virus within the human neurovirulence in mice. nervous system. Interestingly, in pseudorabies virus (PRV; BV has attained its reputation as having extreme neu- a porcine alphaherpesvirus), there does appear to be some rovirulence due to the high mortality associated with the virus-specificity in attachment of virions to dynein motor approximately 60 zoonotic cases that have occurred since proteins (for axonal transport) versus kinesin motor proteins its identification 85 years ago. However, for comparison (for axonal and/or dendritic transport) [164]. Binding to HSV causes ∼500 cases of encephalitis each year in the kinesin motors involves the gE (US8), gI (US7), and US9 US, and without treatment is∼70% fatal with only∼5% of proteins of PRV, while tegument proteins UL36, UL37, and patients fully recovering [18], characteristics that are very US3 impart affinity for dynein motors. u Th s, even slightly similar to that of zoonotic BV. The neurovirulence of BV is altered specificity of any of the homologous BV proteins for only apparent when it infects non-macaques. While there macaque versus human dynein or kinesin motor proteins are some differences between HSV and BV, to date no could affect the neurovirulence of BV in humans by altering differences in the replication of BV in vitro in human versus the spread of infection from that which occurs in the natural macaque cells have been identified that might account for the macaque host. The failure to establish latency in human divergent neurovirulence of BV in these two species. Given neurons, altered stability of latency, and altered spread of the delicate balance that exists in neurons between repression the virus within the nervous system are all consistent with of gene expression to establish latency and lytic replication, the very serious CNS infection versus no infection picture of even slight differences in any of the multitude of host-virus zoonotic BV infection that seems to occur in humans. interactions aeff cting this balance could ultimately alter the pathogenesis of BV in a nonnatural host species, resulting in very different outcomes of infection in macaques versus 8. Conclusions humans. Considerably more research into molecular aspects BV is ubiquitous in populations of captive and free-ranging of host-virus interactions in macaque versus human cells, macaques and despite many exposure incidents every year; both epithelial and neural, needs to be pursued to better understand the extreme neurovirulence exhibited by BV in zoonotic infections are extremely rare and have only been documented in North America. Notwithstanding, BV is humans. notorious for its extreme neurovirulence in the handful of humans who have been infected. Biological aspects of BV Ethical Approval infection in its natural macaque host are very similar to that of HSV in humans, including primary replication in Serum samples from humans and monkeys were all collected epithelial tissue, invasion of sensory neurons, establishment under approved Institutional Review Board (human) or of latency in sensory ganglia, and periodic reactivation from Institutional Animal Care and Use Committee (monkey) latencyinresponsetostressallowingtransmissionofthe protocols. virus to a new host. Phylogenetic analysis of the primate alphaherpesviruses suggests that these viruses have likely Conflicts of Interest coevolved with their hosts, not surprising given the exquisite details that must be involved in virus-host interactions to eTh authors declare that there are no conflicts of interest maintain the virus within the nervous system for the lifespan regarding the publication of this article. of its host without serious adverse consequences while still allowing transmission and perpetuation of the virus within the host species. Given that nonhuman primates are our Acknowledgments closest phylogenetic relatives, it is not surprising that BV The authors wish to thank Drs. C. Jones, K. Ohsawa, and should be very much like HSV with regard to the virus-host J. d’Offay for helpful discussions and critical review of this interactions and mechanisms involved in maintaining the manuscript and DA Leib for eIF2 western blots. This work virus-host relationship in a balanced state. eTh orthologous nature of the BV and HSV genomes and similarity of encoded was supported by PHS Grant R24 OD022013. proteins support this. Based on comparative sequence analy- ses, it also appears that BV encodes LATs, miRNAs, and small References RNAs that would be involved in the intricate regulation of viral latency in neurons as in HSV. [1] D. Elmore and R. Eberle, “Monkey B virus (Cercopithecine Duetothehazardousandrestrictivenatureofperforming herpesvirus 1),” Comparative Medicine,vol.58, no.1,pp.11–21, research with infectious BV, very little experimental or 2008. molecular research has been done on this intriguing virus. To [2] J.L.Huff andP.A.Barry,“B-virus(Cercopithecine herpesvirus date the only genetic characteristic that differs dramatically 1) infection in humans and macaques: Potential for zoonotic betweenBVand HSVisthe lack of homologs of theRL1 disease,” Emerging Infectious Diseases,vol.9,no.2,pp.246–250, (𝛾34.5)andORFPgenesinBV.Despitelacking thesegenes, 2003. 12 Advances in Virology [3] S. A. Keeble, G. J. Christofinis, and W. Wood, “Natural Virus-B [20] L. Jones-Engel, G. A. Engel, M. A. Schillaci et al., “Primate- infection in rhesus monkeys,” The Journal of Pathology ,vol.76, to-human retroviral transmission in Asia,” Emerging Infectious no. 1, pp. 189–199, 1958. Diseases, vol. 11, no. 7, pp. 1028–1035, 2005. [4] A. E. Palmer, “Herpesvirus simiae: historical perspective,” [21] R. Eberle and J. K. Hilliard, “Serological evidence for variation in the incidence of herpesvirus infections in different species of Journal of Medical Primatology,pp. 16–99, 1987. apes,” Journal of Clinical Microbiology,vol.27,no.6,pp. 1357– [5] B. J. Weigler, “Biology of B Virus in Macaque and Human Hosts: 1366, 1989. A Review,” Clinical Infectious Diseases,vol.14,no.2,pp.555–567, 1992. [22] R. Eberle, “Evidence for an alpha-herpesvirus indigenous to mountain gorillas.,” Journal of Medical Primatology,vol.21, no. [6] H.T.ZwartouwandE.A. Boulter,“ExcretionofBvirus 5,pp.246–251,1992. in monkeys and evidence of genital infection,” Laboratory Animals,vol.18, no.1,pp. 65–70, 1984. [23] E. Luebcke, E. Dubovi,D.Black,K.Ohsawa, andR.Eberle, “Iso- lation and characterization of a chimpanzee alphaherpesvirus,” [7] H.T.Zwartouw,J.A.Macarthur,E.A.Boulter,J.H.Seamer,J.H. Journal of General Virology,vol.87,no.1,pp.11–19, 2006. Marston, and A. S. Chamove, “Transmission of B virus infection between monkeys especially in relation to breeding colonies,” [24] S. A. Thompson, J. K. Hilliard, D. Kittel et al., “Retrospective Laboratory Animals,vol.18, no.2,pp.125–130,1984. analysis of an outbreak of B virus infection in a colony of DeBrazza’s monkeys (Cercopithecus neglectus),” Comparative [8] M.R.Andrade,J.Yee,P.Barry etal.,“Prevalenceofantibodies Medicine,vol.50, no.6,pp.649–657, 2000. to selected viruses in a long-term closed breeding colony of rhesus macaques (Macaca mulatta) in Brazil,” American Journal [25] E. L. Blewett, D. Black, and R. Eberle, “Characterization of of Primatology,vol.59,no.3,pp. 123–128,2003. virus-specific and cross-reactive monoclonal antibodies to Her- pesvirus simiae (B virus),” Journal of General Virology,vol.77, [9] R.F.DiGiacomo andK.V.Shah,“Virtualabsenceofinfection no. 11, pp. 2787–2793, 1996. with Herpesvirus simiae in colony-reared rhesus monkeys (Macaca mulatta), with a literature review on antibody preva- [26] K.M.Rogers,D.H.Black,andR. Eberle,“Primarymouse lence in natural and laboratory rhesus populations.,” Laboratory dermal bro fi blast cell cultures as an in vitro model system for Animals,vol.22, no.1,pp. 61–67, 1972. the differential pathogenicity of cross-species herpesvirus papio 2 infections,” Archives of Virology,vol.152,no. 3,pp.543–552, [10] K.Jensen,F.Alvarado-Ramy,J.Gonzalez-M ´ art´ınez, E. Kraisel- burd, and J. Rullan, ´ “B-Virus and Free-Ranging Macaques, Puerto Rico,” Emerging Infectious Diseases,vol.10, no.3,pp. [27] S. A. Keeble, “B virus infection in monkeys,” Annals of the New 494–496, 2004. York Academy of Sciences,vol.85, no.3,pp. 960–969, 1960. [11] L. Jones-Engel, G. A. Engel, J. Heidrich et al., “Temple monkeys [28] E. A. Boulter, “eTh isolation of Monkey B virus (Herpesvirus and health implications of commensalism, Kathmandu, Nepal,” simiae) from the trigeminal ganglia of a healthy seropositive Emerging Infectious Diseases,vol.12, no.6,pp.900–906, 2006. rhesus monkey,” Journal of Biological Standardization,vol.3,no. 3,pp.279-280,1975. [12] M. J. Kessler and J. K. Hilliard, “Seroprevalence of B Virus (Herpesvirus simiae) antibodies in a naturally formed group of [29] J. L. Melnick and D. D. Banker, “Isolation of B virus (herpes rhesus macaques,” Journal of Medical Primatology,vol.19,no.2, group) from the central nervous system of a rhesus monkey,” pp. 155–160, 1990. eTh Journal of Experimental Medicine ,vol.100,no. 2, pp.181– 194, 1954. [13] F.Lee,Y.-J.Lin,M.-C.Deng,T.-Y.Lee,andC.-C.Huang,“Preva- lence of antibody reaction with cercopithecine herpesvirus 1 [30] A. D. Vizoso, “Recovery of herpes simiae (B virus) from both antigen in Macaca cyclopis, Macaca fascicularis, and Papio primary and latent infections in rhesus monkeys,” Journal of anubis in Taiwan,” Journal of Medical Primatology,vol.36, no. Experimental Pathology, vol. 56, no. 6, pp. 485–488, 1975. 6, pp. 343–347, 2007. [31] D.C. Anderson,R.B.Swenson,J.L.Orkin, S.S.Kalter,and H. [14] M.-H. Lee, M. K. Rostal, T. Hughes et al., “Macacine herpesvirus M. McClure, “Primary Herpesvirus simiae (B-virus) infection 1 in long-tailed macaques, Malaysia, 2009-2011,” Emerging in infant macaques,” Laboratory Animals,vol.44,no.5,pp. 526– Infectious Diseases, vol. 21, no. 7, pp. 1107–1113, 2015. 530, 1994. [15] Q. Lin, G.-L. Yuan, L. Ai, J. Li, and H.-L. Li, “Seroprevalence of [32] C.S.Carlson,M. G. O’Sullivan,M.J.Jayoetal.,“FatalDis- BV (Macacine herpesvirus 1) in bred cynomolgus monkeys in seminated Cercopithecine Herpesvirus 1 (Herpes B) Infection Cambodia,” Journal of Veterinary Medical Science,vol.74, no.3, in Cynomolgus Monkeys (Macaca fascicularis),” Veterinary pp.355-356,2012. Pathology, vol. 34, no. 5, pp. 405–414, 1997. [16] R. P. Orcutt,G.J.Pucak,H.L.Foster, J. T. Kilcourse,andT. [33] M. D. Daniel, F. G. Garcia, L. V. Melendez, R. D. Hunt, J. Ferrell, “Multiple testing for the detection of B virus antibody O’Connor, and D. Silva, “Multiple Herpesvirus simiae isolation in specially handled rhesus monkeys aeft r capture from virgin from a rhesus monkey which died of cerebral infarction,” trapping grounds,” Laboratory Animals,vol.26,no.1,pp. 70–74, Laboratory Animals,vol.25,no.3,pp.303–308,1975. [34] M. A. Simon, M. D. Daniel, D. Lee-Parritz, N. W. King, and [17] B. J. Weigler, J. A. Roberts, D. W. Hird, N. W. Lerche, and J. D. J. Ringler, “Disseminated B virus infection in a cynomolgus K. Hilliard, “A cross sectional survey for B virus antibody in a monkey,” Laboratory Animals,vol.43, no.6,pp.545–550, 1993. colony of group housed rhesus macaques,” Laboratory Animals, [35] J.L.Hu,R ff .Eberle,J.Capitanio,S.S.Zhou, andP.A.Barry, vol. 40, no. 3, pp. 257–261, 1990. “Differential detection of B virus and rhesus cytomegalovirus [18] R. J. Whitley and J. W. Gnann, “Viral encephalitis: familiar in rhesus macaques,” JournalofGeneral Virology,vol.84, no.1, infections and emerging pathogens,” The Lancet , vol. 359, no. pp.83–92,2003. 9305, pp. 507–513, 2002. [36] B. J. Weigler, D. W. Hird, J. K. Hilliard et al., “Epidemiology of [19] G. A. Engel, L. Jones-Engel, M. A. Schillaci et al., “Human expo- Cercopithecine Herpesvirus 1 (B Virus) Infection and Shedding sure to herpesvirus B-seropositive Macaques, Bali, Indonesia,” in a Large Breeding Cohort of Rhesus Macaques,” The Journal of Emerging Infectious Diseases,vol.8,no.8, pp.789–795,2002. Infectious Diseases, vol. 167, no. 2, pp. 257–263, 1993. Advances in Virology 13 [37] E.C. Weir,P.N.Bhatt,R.O.Jacoby,J.K.Hilliard,and [54] J. Fierer, P. Bazeley, and A. I. Braude, “Herpes B virus S. Morgenstern, “Infrequent shedding and transmission of encephalomyelitis presenting as ophthalmic zoster: A possible Herpesvirus simiae from seropositive macaques,” Laboratory latent infection reactivated,” Annals of Internal Medicine,vol.79, Animals,vol.43,no.6,pp. 541–544,1993. no. 2, pp. 225–228, 1973. [38] G.J.Chellman,V.S.Lukas,E.M.Eugui,K.P.Altera, S.J. [55] C. Calvo, S. Friedlander, J. K. Hilliard et al., “Case Report: Reac- Almquist, and J. K. Hilliard, “Activation of B virus (Herpesvirus tivation of latent B virus (Macacine herpesvirus 1) presenting simiae) in chronically immunosuppressed cynomolgus mon- as bilateral uveitis, retinal vasculitis and necrotizing herpetic keys,” Laboratory Animals,vol.42, no.2,pp.146–151, 1992. retinitis,” Investigative Ophthalmology & Visual Science,pp. 52– [39] F. Mitsunaga, S. Nakamura, T. Hayashi, and R. Eberle, “Changes 2975, 2011. in the titer of anti-B virus antibody in captive macaques [56] A. G. Freifeld, J. Hilliard, J. Southers et al., “A controlled (Macaca fuscata, M. mulatta, M. fascicularis),” Comparative seroprevalence survey of primate handlers for evidence of Medicine, vol. 57, no. 1, pp. 120–124, 2007. asymptomatic herpes b virus infection,” The Journal of Infectious [40] F. P. Gay and M. Holden, “The herpes encephalitis problem, ii,” Diseases,vol.171,no. 4,pp.1031–1034,1995. The Journal of Infectious Diseases ,vol.53, no.3,pp. 287–303, [57] K. L. Craig, M. K. Hasan, D. L. Jackson et al., “A seminomadic population in Bangladesh with extensive exposure to macaques [41] J. D. Pimentel, “Herpes B virus – “B” is for Brebner: Dr. William does not exhibit high levels of zoonotic simian foamy virus Bartlet Brebner (1903-1932),” Canadian Medical Association infection,” Journal of Virology, vol. 89, no. 14, pp. 7414–7416, Journal,vol.178,no. 6,pp.734-734,2008. [42] A. B. Sabin, “Acute ascending myelitis following a monkey bite, [58] W.F.Johnston,J.Yeh,R.Nierenberg, andG.Procopio, with the isolation of a virus capable of reproducing the disease,” “Exposure to Macaque Monkey Bite,” The Journal of Emergency eTh JournalofExperimentalMedicine ,vol.59, no.2,pp. 115–136, Medicine,vol.49, no.5,pp. 634–637, 2015. [59] M. A. Schillaci, L. Jones-Engel, G. A. Engel et al., “Prevalence [43] Fatal Cercopithecine herpesvirus 1 (B virus) infection following of enzootic simian viruses among urban performance monkeys a mucocutaneous exposure and interim recommendations for in Indonesia,” Tropical Medicine & International Health,vol.10, worker protection, MMWR 47:1073-1076, 1083, 1998. no.12, pp.1305–1314,2005. [44] A. W. Artenstein, C. B. Hicks, B. S. Goodwin Jr., and J. K. [60] P. Gautret, B. Jesse, L. Dacheux et al., “Correction to: Rabies Hilliard, “Human infection with B virus following a needlestick in Nonhuman Primates and Potential for Transmission to injury,” ReviewsofInfectiousDiseases,vol.13,no.2,pp. 288–291, Humans: A Literature Review and Examination of Selected French National Data (PLoS Negl Trop Dis, 9, 5),” PLOS [45] D. S. Davenport, D. R. Johnson, G. P. Holmes, D. A. Jewett, S. C. Neglected Tropical Diseases, vol. 9, no. 5, Article ID e0003799, Ross, and J. K. Hilliard, “Diagnosis and management of human b virus (herpesvims simiae) infections in michigan,” Clinical Infectious Diseases,vol.19,no.1,pp. 33–41,1994. [61] G. A. Engel, C. T. Small, K. Soliven et al., “Zoonotic simian foamy virus in Bangladesh reflects diverse patterns of transmis- [46] W. L. Davidson and K. Hummeler, “B Virus Infection in Man,” sion and co-infection,” Emerging Microbes & Infections,vol.2, Annals of the New York Academy of Sciences,vol.85, no.3,pp. no.9,pp. e58–e58, 2013. 970–979, 1960. [47] G.P. Holmes,J.K.Hilliard,K.C.Klontzetal.,“Bvirus(Her- [62] A. Fuentes and S. Gamerl, “Disproportionate participation pesvirus simiae) infection in humans: Epidemiologic investiga- by age/sex classes in aggressive interactions between long- tion of a cluster,” Annals of Internal Medicine, vol. 112, no. 11, pp. tailed macaques (Macaca fascicularis) and human tourists at 833–839, 1990. Padangtegal monkey forest, Bali, Indonesia,” American Journal of Primatology,vol.66,no.2,pp. 197–204,2005. [48] K. Hummeler, W. L. Davidson, W. Henle, A. C. Laboc- cetta, and H. G. Ruch, “Encephalomyelitis due to infection [63] B. P. Wheatley, eTh Sacred Monkeys of Bali, Waveland Press, with Herpesvirus simiae (herpes B virus); a report of two Prospect Heights, IL, USA, 1999. fatal, laboratory-acquired cases,” eTh New England Journal of [64] L. E. Mease and K. A. Baker, “Monkey bites among US military Medicine,vol.261,no. 2,pp.64–68,1959. members, Afghanistan, 2011,” Emerging Infectious Diseases,vol. [49] F. P. Nagler and M. Klotz, “A fatal B virus infection in a 18, no. 10, pp. 1647–1649, 2012. person subject to recurrent herpes labialis,” Canadian Medical [65] N. J. Riesland and H. Wilde, “Expert Review of Evidence Bases Association Journal,pp.79–743,1958. for Managing Monkey Bites in Travelers,” Journal of Travel [50] J. M. M. Nsabimana, M. Moutschen, E. Thiry, and F. Meurens, Medicine, vol. 22, no. 4, pp. 259–262, 2015. Cahiers/Sante´, Infection humaine par le virus B du singe en [66] A.M. Bennett,M. J.Slomka,D.W.G.Brown,G.Lloyd,and M. Afrique. CahiersSante1,3-8,2008. Mackett, “Protection against herpes B virus infection in rabbits [51] R. J. Whitely, J. K. Hilliard, Cercopithecine herpesvirus (B with a recombinant vaccinia virus expressing glycoprotein D,” virus), In: D. M. Knipe, P. M. Howley (eds) Fields Virology, Journal of Medical Virology,vol.57, no.1,pp.47–56,1999. Lippincott Williams and Wilkins, Philadelphia, PA, USA, pp 2835-2848, 2001. [67] E. A. Boulter and D. P. Grant, “Latent infection of monkeys with B virus and prophylactic studies in a rabbit model of this [52] G. E. Breen, S. G. Lamb, and A. T. Otaki, “Monkey-bite disease,” Journal of Antimicrobial Chemotherapy,vol.3,pp.107– encephalomyelitis report of a case—with recovery,” British 113, 1977. Medical Journal,vol.2,no. 5087,pp. 22-23,1958. [53] B. L. Bryan, C. D. Espana, R. W. Emmons, N. Vijayan, and [68] E. A. Boulter, H. T. Zwartouw, and B. Thornton, “Postexposure P. D. Hoeprich, “Recovery from encephalomyelitis caused by immunoprophylaxis against B virus (herpesvirus simiae) infec- herpesvirus simiae: report of a case,” JAMA Internal Medicine, tion,”BritishMedicalJournal(ClinicalResearched.),vol.283,no. vol. 135, no. 6, pp. 868–870, 1975. 6305, p. 1495, 1981. 14 Advances in Virology [69] R. N. Hull and J. C. Nash, “Immunization against b virus human and simian sera induced by herpes simplex and related infection: Preparation of an experimental vaccine,” American simian viruses,” Journal of Virological Methods,vol.14,no.2,pp. Journal of Epidemiology,vol.71, no.1,pp. 15–28,1960. 99–109, 1986. [85] Y. Ueda, I. Tagaya, and K. Shiroki, “Immunological relationship [70] L. Perelygina, I. Patrusheva, H. Zurkuhlen, and J. K. Hilliard, “Characterization of B virus glycoprotein antibodies induced by between herpes simplex virus and B virus,” Archiv fur die Gesamte Virusforschung,vol.24,no.3,pp.231–244,1968. DNA immunization,” Archives of Virology,vol.147,no. 11, pp. 2057–2073, 2002. [86] E. A. Boulter, S. S. Kalter, R. L. Heberling, J. E. Guajardo, and T. L. Lester, “A comparison of neutralization tests for [71] G. Gosztonyi, D. Falke, and H. Ludwig, “Axonal and transsy- the detection of antibodies to Herpesvirus simiae (monkey B naptic (transneuronal) spread of Herpesvirus simiae (B virus) virus),” Laboratory Animals,vol.32,no.2,pp. 150–152,1982. in experimentally infected mice,” Histology and Histopathology, vol. 7, no.1,pp. 63–74, 1992. [87] R. Eberle, D. Black, and J. K. Hilliard, “Relatedness of glyco- proteins expressed on the surface of simian herpesvirus virions [72] G. Gosztonyi, D. Falke, and H. Ludwig, “Axonal-transsynaptic and infected cells to specific HSV glycoproteins,” Archives of spread as the basic pathogenetic mechanism in B virus infection Virology,vol.109,no. 3-4,pp.233–252,1989. of the nervous system.,” Journal of Medical Primatology,vol.21, no. 1, pp. 42-43, 1992. [88] R.D.Henkel,H.M.McClure,P.Krug,D.Katz,andJ.K.Hilliard, “Serological evidence of alpha herpesvirus infection in sooty [73] J. W. Ritchey, M. E. Payton, and R. Eberle, “Clinicopathological mangabeys,” Journal of Medical Primatology,vol.31, no.3,pp. characterization of monkey B virus (cercopithecine herpesvirus 120–128, 2002. 1) infection in mice,” Journal of Comparative Pathology,vol.132, [89] B. Roizman, “eTh Herpesviruses. Albert S. Kaplan, Ed. Aca- no. 2-3, pp. 202–217, 2005. demic Press, New York, 1973. xvi, 740 pp., illus. %1,” Science,vol. [74] K. M.Rogers,J.W.Ritchey,M.Payton, D. H.Black, andR. 184, no. 4143, pp. 1277-1278, 1974. Eberle, “Neuropathogenesis of herpesvirus papio 2 in mice [90] S.-W. Mou, J. K. Hilliard, C.-H. Song, and R. Eberle, “Compar- parallels infection with Cercopithecine herpesvirus 1 (B virus) ison of the primate alphaherpesviruses - I. Characterization of in humans,” JournalofGeneralVirology,vol.87, no.2,pp. 267– two Herpesviruses from spider monkeys and squirrel monkeys 276, 2006. and viral polypeptides synthesized in infected cells,” Archives of [75] D. Black, J. Ritchey, M. Payton, and R. Eberle, “Role of the Virology, vol. 91, no. 1-2, pp. 117–133, 1986. virion host shutoff protein in neurovirulence of monkey B virus [91] D. J. McGeoch, F. J. Rixon, and A. J. Davison, “Topics in (Macacine herpesvirus 1),” Virologica Sinica,vol.29,no.5,pp. herpesvirus genomics and evolution,” Virus Research,vol.117, 274–283, 2014. no.1,pp. 90–104,2006. [76] L. A. Brush, D. H. Black, K. A. McCormack et al., “Papiine her- [92] A. Severini, S. D. Tyler, G. A. Peters, D. Black, and R. Eberle, pesvirus 2 as a predictive model for drug sensitivity of Macacine “Genome sequence of a chimpanzee herpesvirus and its relation herpesvirus 1 (monkey B virus),” Comparative Medicine,vol.64, to other primate alphaherpesviruses,” Archives of Virology,vol. no. 5, pp. 386–393, 2014. 158, no. 8, pp. 1825–1828, 2013. [77] R. Eberle,L.K.Maxwell,S.Nicholson,D.Black,andL. Jones- [93] J. O. Wertheim, M. D. Smith, D. M. Smith, K. Scheffler, and Engel, “Genome sequence variation among isolates of monkey S. L. Kosakovsky Pond, “Evolutionary origins of human herpes B virus (Macacine alphaherpesvirus 1) from captive macaques,” simplex viruses 1 and 2,” Molecular Biology and Evolution,vol. Virology,vol.508,pp. 26–35, 2017. 31, no. 9, pp. 2356–2364, 2014. [78] E. A. Kurt-Jones, M. Chan, S. Zhou et al., “Herpes simplex [94] A.Arvin,G. Campadelli-Fiume,E.Mocarskietal.,“Human virus 1 interaction with Toll-like receptor 2 contributes to lethal herpesviruses: Biology, therapy, and immunoprophylaxis,” encephalitis,” Proceedings of the National Acadamy of Sciences of Human Herpesviruses: Biology, er Th apy, and Immunoprophy- the United States of America,vol.101,no. 5,pp.1315–1320,2004. laxis,pp. 1–1410,2007. [79] P.Lundberg,C.Ramakrishna,J.Brown et al., “ei Th mmune [95] J. K.Hilliard,R.Eberle, S.L. Lipper,R.M.Munoz,and S. response to herpes simplex virus type 1 infection in susceptible A. Weiss, “Herpesvirus simiae (B virus): Replication of the miceisamajorcauseof centralnervoussystempathology virus and identification of viral polypeptides in infected cells,” resulting in fatal encephalitis,” Journal of Virology,vol.82, no. Archives of Virology,vol.93, no.3-4,pp.185–198,1987. 14, pp. 7078–7088, 2008. [96] R. N. Hull, “B virus vaccine,” Laboratory Animal Science,vol.21, [80] K.M. Rogers,K.A.Ealey,J.W.Ritchey,D.H.Black,andR. pp. 1068–1071, 1971. Eberle, “Pathogenicity of different baboon Herpesvirus papio [97] K.Ohsawa,D.H.Black,H.Sato, andR.Eberle, “Sequence 2 isolates is characterized by either extreme neurovirulence or and genetic arrangement of the Us region of the monkey B complete apathogenicity,” JournalofVirology,vol.77, no.20, pp. virus (Cercopithecine Herpesvirus 1) genome and comparison 10731–10739, 2003. with the Us regions of other primate herpesviruses,” Journal of [81] B. V. Troan, L. Perelygina, I. Patrusheva et al., “Naturally Virology,vol.76,no.3,pp.1516–1520, 2002. transmitted herpesvirus papio-2 infection in a black and white [98] K. Ohsawa,D.H.Black,H.Sato, K.Rogers,andR. Eberle, colobus monkey,” Journal of the American Veterinary Medical “Sequence and genetic arrangement of the UL region of the Association,vol.231,no. 12,pp.1878–1883, 2007. monkey B virus (Cercopithecine herpesvirus 1) genome and [82] R. Eberle and J. Hilliard, “eTh simian herpesviruses,” Infectious comparison with the UL region of other primate herpesviruses,” Agents and Disease, vol. 4, no. 2, pp. 55–70, 1995. Archives of Virology,vol.148,no. 5,pp.989–997,2003. [83] J. K.Hilliard,D.Black,andR. Eberle,“Simian alphaher- [99] L. Perelygina,L.Zhu,H.Zurkuhlen,R.Mills,M. Borodovsky, pesviruses and their relation to the human herpes simplex andJ.K.Hilliard,“Completesequenceandcomparativeanalysis viruses,” Archives of Virology,vol.109,no. 1-2, pp.83–102,1989. of the genome of herpes B virus (Cercopithecine herpesvirus 1) [84] D. Katz,J.K.Hilliard,R.Eberle,andS.L.Lipper,“ELISA for from a rhesus monkey,” Journal of Virology,vol.77,no.11, pp. detection of group-common and virus-specific antibodies in 6167–6177, 2003. Advances in Virology 15 [100] K. Ohsawa, D. Black, M. Ohsawa, and R. Eberle, “Genome [115] G. L. Van Hoosier Jr. and J. L. Melnick, “Neutralizing antibodies sequence of a pathogenic isolate of monkey B virus (species in human sera to Herpesvirus simiae (B virus),” Texas Reports Macacine herpesvirus 1),” Archives of Virology,vol.159,no.10, on Biology and Medicine,vol.19, pp.376–380,1961. pp.2819–2821,2014. [116] D. Katz, W. Shi, M. S. Gowda et al., “Identification of unique B virus (Macacine Herpesvirus 1) epitopes of zoonotic and [101] K. Ohsawa, D. H. Black, R. Torii, H. Sato, and R. Eberle, “Detec- tion of a unique genotype of monkey B virus (Cercopithecine macaque isolates using monoclonal antibodies,” PLoS ONE,vol. herpesvirus 1) indigenous to native Japanese macaques (Macaca 12, no. 8, Article ID e0182355, 2017. fuscata),” Comparative Medicine,vol.52,no.6,pp.555–559, [117] I. Patrusheva, L. Perelygina, I. Torshin, J. LeCher, and J. Hilliard, “B virus (Macacine herpesvirus 1) divergence: Variations in glycoprotein D from clinical and laboratory isolates diversify [102] A.L.Smith,D.H.Black,andR. Eberle,“Molecularevidence virus entry strategies,” Journal of Virology,vol.90, no.20,pp. for distinct genotypes of monkey B virus (herpesvirus simiae) 9420–9432, 2016. which are related to the macaque host species,” Journal of Virology, vol. 72, no. 11, pp. 9224–9232, 1998. [118] E. Linwood Blewett, J. T. Saliki, and R. Eberle, “Development of a competitive ELISA for detection of primates infected with [103] M. A. Amen and A. Griffiths, “Identification and expression monkey B virus (Herpesvirus simiae),” JournalofVirological analysis of herpes B virus-encoded small RNAs,” Journal of Methods,vol.77,no.1,pp. 59–67, 1999. Virology, vol. 85, no. 14, pp. 7296–7311, 2011. [119] L. M. Cropper,D.N.Lees, R. Patt,I.R.Sharp,andD. Brown, [104] M. I. Besecker, M. E. Harden, G. Li, X.-J. Wang, and A. Gritffi hs, “Monoclonal antibodies for the identification of herpesvirus “Discovery of herpes B virus-encoded MicroRNAs,” Journal of simiae (B virus),” Archives of Virology,vol.123,no. 3-4,pp.267– Virology,vol.83,no.7,pp.3413–3416,2009. 277, 1992. [105] S. D. Tyler, G. A. Peters, and A. Severini, “Complete genome [120] H. P. Huemer, C. Wechselberger, A. M. Bennett, D. Falke, and L. sequence of cercopithecine herpesvirus 2 (SA8) and compari- Harrington, “Cloning and expression of the complement recep- son with other simplexviruses,” Virology,vol.331,no.2,pp.429– tor glycoprotein C from Herpesvirus simiae (herpes B virus): 440, 2005. Protection from complement-mediated cell lysis,” Journal of [106] S. D. Tyler and A. Severini, “The complete genome sequence General Virology,vol.84, no.5,pp. 1091–1100, 2003. of herpesvirus papio 2 (Cercopithecine herpesvirus 16) shows [121] Q.Fan,M.Amen, M. Harden,A.Severini,A.Gritffi hs,andR. evidence of recombination events among various progenitor Longnecker, “Herpes B virus utilizes human nectin-1 but not herpesviruses,” Journal of Virology,vol.80,no.3,pp.1214–1221, HVEM or PILR𝛼 for cell-cell fusion and virus entry,” Journal of Virology,vol.86,no.8,pp. 4468–4476, 2012. [107] R. Eberle and D. H. Black, Molecular aspects of monkey B virus [122] L. Li, Z. Qiu, Y. Li et al., “Herpes B virus gD interaction with and implications for diagnostic test development, Recent Res itshumanreceptor-Aninsilicoanalysisapproach,” Theoretical Devel Virol, vol. 1, pp. 85-94, 1999. Biology and Medical Modelling,vol.11,no.1,article no.27, 2014. [108] L. Perelygina, H. Zurkuhlen, I. Patrusheva, and J. K. Hilliard, [123] C.Boutell andR.D.Everett,“Regulationof alphaherpesvirus “Identification of a herpes B virus-specific glycoprotein D infections by the ICP0 family of proteins,” Journal of General immunodominant epitope recognized by natural and foreign Virology,vol.94,no.3,pp. 465–481,2013. hosts,” The Journal of Infectious Diseases ,vol.186,no. 4,pp.453– [124] K.M.Rogers, R. F.Wolf,G.L.White,and R.Eberle,“Experi- 461, 2002. mental infection of baboons (Papio cynocephalus anubis) with [109] L.Perelygina, I.Patrusheva,S.Hombaiahetal.,“Production apathogenic and neurovirulent subtypes of Herpesvirus papio of herpes B virus recombinant glycoproteins and evaluation of 2,” Comparative Medicine,vol.55, no.5,pp. 425–430, 2005. their diagnostic potential,” Journal of Clinical Microbiology,vol. [125] D.Black,K.Ohsawa, S.Tyler, L.Maxwell, andR.Eberle, “A 43,no. 2,pp.620–628,2005. single viral gene determines lethal cross-species neurovirulence [110] M. J.Slomka,L.Harrington,C. Arnold,J.P.N.Norcott, of baboon herpesvirus HVP2,” Virology,vol.452-453,pp.86–94, andD.W.G.Brown,“Complete nucleotidesequence ofthe herpesvirus simiae glycoprotein G gene and its expression as [126] T. Todo, “Active immunotherapy oncolytic virus therapy using an immunogenic fusion protein in bacteria,” Journal of General Virology,vol.76,no.9,pp. 2161–2168,1995. HSV-1,” Advances in Experimental Medicine and Biology,vol. 746,pp.178–186,2012. [111] K. Tanabayashi, R. Mukai, and A. Yamada, “Detection of B virus [127] J. Conner, J. Macfarlane, H. Lankinen, and H. Marsden, “eTh antibody in monkey sera using glycoprotein D expressed in unique N terminus of the herpes simplex virus type 1 large mammalian cells,” Journal of Clinical Microbiology,vol.39, no. subunit is not required for ribonucleotide reductase activity,” 9, pp. 3025–3030, 2001. Journal of General Virology, vol. 73, no. 1, pp. 103–112, 1992. [112] R. L. Heberling and S. S. Kalter, “A dot-immunobinding assay [128] D. Lembo and W. Brune, “Tinkering with a viral ribonucleotide on nitrocellulose with psoralen inactivated Herpesvirus simiae reductase,” Trends in Biochemical Sciences,vol.34,no.1,pp.25– (B virus).,” Laboratory animal science Chicago,vol.37, no.3,pp. 32, 2009. 304–308, 1987. [129] H.Guo,S.Omoto,P.A.Harrisetal.,“Herpessimplexvirus [113] D. Katz, W. Shi, P. W. Krug, R. Henkel, H. McClure, and J. suppresses necroptosis in human cells,” Cell Host & Microbe,vol. K. Hilliard, “Antibody cross-reactivity of alphaherpesviruses as 17,no.2, pp.243–251,2015. mirrored in naturally infected primates,” Archives of Virology, vol. 147, no. 5, pp. 929–941, 2002. [130] Z. Huang, S.-Q. Wu, Y. Liang et al., “RIP1/RIP3 binding to HSV-1 ICP6 initiates necroptosis to restrict virus propagation [114] D. Katz,W.Shi,P.W.Krug, andJ.K.Hilliard,“Alphaherpesvirus in mice,” Cell Host & Microbe,vol.17, no.2,pp.229–242, 2015. antigen quantitation to optimize the diagnosis of herpes B virus infection,” JournalofVirological Methods,vol.103,no.1,pp.15– [131] X. Wang, Y. Li, S. Liu et al., “Direct activation of RIP3/MLKL- 25, 2002. dependent necrosis by herpes simplex virus 1 (HSV-1) protein 16 Advances in Virology ICP6 triggers host antiviral defense,” Proceedings of the National infection with𝛾134.5- mutants of herpes simplex virus,” Pro- Acadamy of Sciences of the United States of America, vol. 111, no. ceedings of the National Acadamy of Sciences of the United States 43, pp. 15438–15443, 2014. of America,vol.92,no.23, pp.10516–10520,1995. [132] C. A. Bolovan, N. M. Sawtell, and R. L. o Th mpson, “ICP34.5 [145] P.A.M.GobeilandD. A.Leib,“Herpes simplexvirus mutants of herpes simplex virus type 1 strain 17syn+ are gamma34.5 interferes with autophagosome maturation and attenuated for neurovirulence in mice and for replication in antigen presentation in dendritic cells,” mBio,vol.3,no. 5,pp. confluent primary mouse embryo cell cultures,” Journal of e00267–e00212, 2012. Virology,vol.68,no.1,pp.48–55,1994. [146] B. He, M. Gross, and B. Roizman, “The 𝛾134.5 protein of [133] J.Chou,E.R.Kern,R.J.Whitley, andB.Roizman,“Mapping herpes simplex virus 1 complexes with protein phosphatase 1𝛼 of herpes simplex virus-1 neurovirulence to 𝛾134.5, a gene to dephosphorylate the𝛼 subunit of the eukaryotic translation nonessential for growth in culture,” Science,vol.250,no. 4985, initiation factor 2 and preclude the shutoff of protein synthesis pp. 1262–1266, 1990. by double-stranded RNA-activated protein kinase,” Proceedings of the National Acadamy of Sciences of the United States of [134] L. Y. Lee and P. A. Schaer ff , “A virus with a mutation in the ICP4-binding site in the L/ST promoter of herpes simplex virus America, vol. 94, no. 3, pp. 843–848, 1997. type 1, but not a virus with a mutation in open reading frame P, [147] B. He, M. Gross, and B. Roizman, “The 𝛾134.5 Protein of herpes exhibits cell-type-specific expression of 𝛾134.5 transcripts and simplex virus I has the structural and functional attributes of a latency-associated transcripts,” Journal of Virology,vol.72, no. protein phosphatase I regulatory subunit and is present in a high 5, pp. 4250–4264, 1998. molecular weight complex with the enzyme in infected cells,” [135] N. S. Markovitz, D. Baunoch, and B. Roizman, “The range and The Journal of Biological Chemistry ,vol.273,no.33,pp. 20737– distribution of murine central nervous system cells infected 20743, 1998. with the𝛾134.5-Mutantofherpessimplex virus1,” Journal of [148] A. Simmons and A. A. Nash, “Zosteriform spread of herpes Virology,vol.71, no.7,pp. 5560–5569, 1997. simplex virus as a model of recrudescence and its use to [136] B. Roizman and N. Markovitz, “Herpes simplex virus virulence: investigate the role of immune cells in prevention of recurrent the functions of the gamma (1)34.5 gene,” Journal of NeuroVirol- disease,” Journal of Virology,vol.52,no.3,pp. 816–821,1984. ogy,vol.3Suppl,p. S1,1997. [149] Y. Tsalenchuck, T. Tzur, I. Steiner, and A. Panet, “Different [137] R. J. Whitley, E. R. Kern, S. Chatterjee, J. Chou, and B. Roizman, modes of herpes simplex virus type 1 spread in brain and skin “Replication, establishment of latency, and induced reactivation tissues,” Journal of NeuroVirology,vol.20,no.1,pp. 18–27,2014. of herpes simplex virus 𝛾1 34.5 deletion mutants in rodent [150] L. M. Wakim, C. M. Jones, T. Gebhardt, C. M. Preston, and F. R. models,” eTh Journal of Clinical Investigation ,vol.91, no.6,pp. Carbone, “CD8+ T-cell attenuation of cutaneous herpes simplex 2837–2843, 1993. virus infection reduces the average viral copy number of the [138] D. Phelan, E. R. Barrozo, and D. C. Bloom, “HSV1 latent ensuing latent infection,” Immunology & Cell Biology,vol.86, transcription and non-coding RNA: A critical retrospective,” no.8,pp.666–675,2008. Journal of Neuroimmunology,vol.308,pp. 65–101,2017. [151] M. Yamada, Y. Arao, F. Uno, and S. Nii, “Mechanism of Differ- [139] G. Cheng, M.-E. Brett, and B. He, “Val193 and Phe195 of the ences in Pathogenicity between Two Variants of a Laboratory 𝛾134.5 protein of herpes simplex virus 1 are required for viral Strain of Herpes Simplex Virus Type 1,” Microbiology and resistance to interferon-𝛼/𝛽,” Virology,vol.290,no. 1, pp.115– Immunology, vol. 30, no. 12, pp. 1259–1270, 1986. 120, 2001. [152] Y. Minamishima and Y. Eizuru, “Susceptibility of Primate [140] X. Jing, M. Cerveny, K. Yang, and B. He, “Replication of herpes Diploid Cells to Human Herpesviruses,” Microbiology and simplex virus 1 depends on the𝛾134. 5 functions that facilitate Immunology, vol. 21, no. 11, pp. 667–671, 1977. virus response to interferon and egress in the different stages [153] S. Nii, “Abortive infection of LLC-MK2 cells by Herpes simplex of productive infection,” Journal of Virology, vol. 78, no. 14, pp. virus.,” Biken Journal, Journal of the Research Institute for 7653–7666, 2004. Microbial Diseases,vol.15, no.1,pp. 43–47, 1972. [141] J. Trgovcich, D. Johnson, and B. Roizman, “Cell surface major [154] M. Yamada, “Replication of herpes simplex virus in two cell histocompatibility complex class II proteins are regulated by the systems derived from rhesus monkeys,” Biken Journal, Journal products of the𝛾34.5 and UL41 genes of herpes simplex virus 1,” of the Research Institute for Microbial Diseases,vol.26,no.1,pp. Journal of Virology, vol. 76, no. 14, pp. 6974–6986, 2002. 35–47, 1983. [142] J. Chou and B. Roizman, “eTh 𝛾134.5 gene of herpes simplex [155] L. Perelygina, I. Patrusheva, M. Vasireddi, N. Brock, and J. virus 1 precludes neuroblastoma cells from triggering total Hilliard, “Virus (Macacine herpesvirus 1) glycoprotein D is shutoff of protein synthesis characteristic of programed cell functional but dispensable for virus entry into macaque and death in neuronal cells,” Proceedings of the National Acadamy of humanskincells,” Journal of Virology,vol.89,no.10, pp.5515– Sciences of the United States of America,vol.89,no.8,pp.3266– 5524, 2015. 3270, 1992. [156] M. L. van de Weijer, R. D. Luteijn, and E. J. H. J. Wiertz, “Viral [143] J. Chou and B. Roizman, “Herpes simplex virus 1𝛾134.5 gene immune evasion: Lessons in MHC class I antigen presentation,” function, which blocks the host response to infection, maps in Seminars in Immunology,vol.27,no.2,pp.125–137,2015. the homologous domain of the genes expressed during growth arrest and DNA damage,” Proceedings of the National Acadamy [157] M. Vasireddi and J. Hilliard, “Herpes B virus, macacine her- pesvirus 1, breaks simplex virus tradition via major histocom- of Sciences of the United States of America,vol.91,no.12,pp. 5247–5251, 1994. patibility complex class I expression in cells from human and macaque hosts,” Journal of Virology,vol.86,no.23,pp.12503– [144] J. Chou, J.-J. Chen, M. Gross, and B. Roizman, “Association of 12511, 2012. a Mr 90,000 phosphoprotein with protein kinase PKR in cells exhib [158] M. Vasireddi and J. K. Hilliard, “Regulation of PI3K/Akt iting enhanced phosphorylation of translation initiation factor eIF-2𝛼 and premature shutoff of protein synthesis after dependent apoptotic markers during b virus infection of human Advances in Virology 17 and macaque fibroblasts,” PLoS ONE,vol.12, no.5,ArticleID e0178314, 2017. [159] B. Roizman, G. Zhou, and T. Du, “Checkpoints in productive and latent infections with herpes simplex virus 1: conceptual- ization of the issues.,” Journal of NeuroVirology,vol.17, no.6, pp.512–517,2011. [160] B.Roizman andR.J.Whitley,“Aninquiryintothemolecular basis of HSV latency and reactivation,” Annual Review of Microbiology,vol.67,pp.355–374,2013. [161] S. Efstathiou and C. M. Preston, “Towards an understanding of themolecular basisofherpessimplexviruslatency,” Virus Research, vol. 111, no. 2, pp. 108–119, 2005. [162] W.A.Blyth,D.A.Harbour,and T. J. Hill,“Pathogenesisof zosteriform spread of herpes simplex virus in the mouse,” Journal of General Virology,vol.65,no.9,pp.1477–1486,1984. [163] B. Roizman and G. Zhou, “eTh 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry,” Virology,vol. 479-480, pp. 562–567, 2015. [164] T. Kramer and L. W. Enquist, “Directional spread of alphaher- pesviruses in the nervous system,” Viruses,vol.5,no.2,pp.678– 707, 2013. 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References (172)

B. He, M. Gross, B. Roizman (1998)
The γ134.5 Protein of Herpes Simplex Virus 1 Has the Structural and Functional Attributes of a Protein Phosphatase 1 Regulatory Subunit and Is Present in a High Molecular Weight Complex with the Enzyme in Infected Cells*
The Journal of Biological Chemistry, 273
Karen Craig, M. Hasan, Dana Jackson, G. Engel, Khanh Soliven, M. Feeroz, Xiaoxing Wang, L. Jones-Engel, M. Linial (2015)
A Seminomadic Population in Bangladesh with Extensive Exposure to Macaques Does Not Exhibit High Levels of Zoonotic Simian Foamy Virus Infection
Journal of Virology, 89
Dane Phelan, Enrico Barrozo, D. Bloom (2017)
HSV1 latent transcription and non-coding RNA: A critical retrospective
Journal of Neuroimmunology, 308
R. Hull (1971)
B virus vaccine.
Laboratory animal science, 21 6
A. Bennett, M. Slomka, David Brown, G. Lloyd, M. Mackett (1999)
Protection against herpes B virus infection in rabbits with a recombinant vaccinia virus expressing glycoprotein D
Journal of Medical Virology, 57
Joany Chou, Bernard Roizman (1994)
Herpes simplex virus 1 gamma(1)34.5 gene function, which blocks the host response to infection, maps in the homologous domain of the genes expressed during growth arrest and DNA damage.
Proceedings of the National Academy of Sciences of the United States of America, 91 12
J. Trgovcich, David Johnson, B. Roizman (2002)
Cell Surface Major Histocompatibility Complex Class II Proteins Are Regulated by the Products of the γ134.5 and UL41 Genes of Herpes Simplex Virus 1
Journal of Virology, 76
Emily Luebcke, E. Dubovi, D. Black, K. Ohsawa, R. Eberle (2006)
Isolation and characterization of a chimpanzee alphaherpesvirus.
The Journal of general virology, 87 Pt 1
G. Cheng, M. Brett, B. He (2001)
Val193 and Phe195 of the γ134.5 Protein of Herpes Simplex Virus 1 Are Required for Viral Resistance to Interferon-α/β
Virology, 290
E. Kurt-Jones, M. Chan, Shenghua Zhou, Jennifer Wang, G. Reed, R. Bronson, M. Arnold, D. Knipe, R. Finberg (2004)
Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis.
Proceedings of the National Academy of Sciences of the United States of America, 101 5
L. Perelygina, Li Zhu, H. Zurkuhlen, Ryan Mills, M. Borodovsky, J. Hilliard (2003)
Complete Sequence and Comparative Analysis of the Genome of Herpes B Virus (Cercopithecine Herpesvirus 1) from a Rhesus Monkey
Journal of Virology, 77
Mei-Ho Lee, M. Rostal, Tom Hughes, F. Sitam, Chee-Yen Lee, J. Japning, Mallory Harden, A. Griffiths, M. Basir, N. Wolfe, J. Epstein, P. Daszak (2015)
Macacine Herpesvirus 1 in Long-Tailed Macaques, Malaysia, 2009–2011
Emerging Infectious Diseases, 21
K. Ohsawa, D. Black, M. Ohsawa, R. Eberle (2014)
Genome sequence of a pathogenic isolate of monkey B virus (species Macacine herpesvirus 1)
Archives of Virology, 159
S. Tyler, G. Peters, A. Severini (2005)
Complete genome sequence of cercopithecine herpesvirus 2 (SA8) and comparison with other simplexviruses.
Virology, 331 2
M. Schillaci, L. Jones-Engel, G. Engel, Y. Paramastri, E. Iskandar, B. Wilson, J. Allan, R. Kyes, R. Watanabe, R. Grant (2005)
Prevalence of enzootic simian viruses among urban performance monkeys in Indonesia
Tropical Medicine & International Health, 10
D. McGeoch, F. Rixon, A. Davison (2006)
Topics in herpesvirus genomics and evolution.
Virus research, 117 1
K. Jensen, F. Alvarado-Ramy, J. Gonzalez-Martinez, E. Kraiselburd, J. Rullán (2004)
B-Virus and Free-Ranging Macaques, Puerto Rico
Emerging Infectious Diseases, 10
M. Weijer, R. Luteijn, E. Wiertz (2015)
Viral immune evasion: Lessons in MHC class I antigen presentation.
Seminars in immunology, 27 2
大沢一貴 (2002)
Sequence and genetic arrangement of the Us region of the monkey B virus(Cercopithecine herpesvirus 1)genome and comparison with the Us regions of other primate herpesviruses
B. Roizman, Guoying Zhou (2015)
The 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry.
Virology, 479-480
D. Elmore, R. Eberle (2008)
Monkey B virus (Cercopithecine herpesvirus 1).
Comparative medicine, 58 1
L. Wakim, Claerwen Jones, T. Gebhardt, C. Preston, F. Carbone (2008)
CD8+ T‐cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection
Immunology and Cell Biology, 86
Weigler Bj, D. Hird, J. Hilliard, N. Lerche, J. Roberts, L. Scott (1993)
Epidemiology of cercopithecine herpesvirus 1 (B virus) infection and shedding in a large breeding cohort of rhesus macaques.
The Journal of infectious diseases, 167 2
M. Yamada, Y. Arao, F. Uno, S. Nii (1986)
Mechanism of Differences in Pathogenicity between Two Variants of a Laboratory Strain of Herpes Simplex Virus Type 1
Microbiology and Immunology, 30
J. Fierer, P. Bazely, A. Braude (1973)
Herpes B virus encephalomyelitis presenting as ophthalmic zoster. A possible latent infection reactivated.
Annals of internal medicine, 79 2
(2012)
Herpes simplex virus gamma34.5 interferes with autophagosome maturation and antigen presentation in dendritic cells
G. Breen, S. Lamb, A. Otaki (1958)
Monkey-bite encephalomyelitis; report of a case; with recovery.
British medical journal, 2 5087
J. Chou, B. Roizman
The y134.5 gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells
Identiﬁcation and Expression Analysis of Herpes B Virus-Encoded Small RNAs (cid:1)
P. Gautret, Jesse Blanton, L. Dacheux, F. Ribadeau-Dumas, P. Brouqui, P. Parola, Douglas Esposito, H. Bourhy (2014)
Correction: Rabies in Nonhuman Primates and Potential for Transmission to Humans: A Literature Review and Examination of Selected French National Data
PLoS Neglected Tropical Diseases, 9
P. Lundberg, C. Ramakrishna, D. Hinton, H. Openshaw, E. Cantin (2008)
The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis
Journal of Virology, 82
J. Melnick, D. Banker (1954)
ISOLATION OF B VIRUS (HERPES GROUP) FROM THE CENTRAL NERVOUS SYSTEM OF A RHESUS MONKEY
The Journal of Experimental Medicine, 100
S. Thompson, J. Hilliard, D. Kittel, S. Lipper, W. Giddens, D. Black, R. Eberle (2000)
Retrospective analysis of an outbreak of B virus infection in a colony of DeBrazza's monkeys (Cercopithecus neglectus).
Comparative medicine, 50 6
N. Markovitz, D. Baunoch, B. Roizman (1997)
The range and distribution of murine central nervous system cells infected with the gamma(1)34.5- mutant of herpes simplex virus 1
Journal of Virology, 71
D. Katz, W. Shi, P. Krug, R. Henkel, H. McClure, J. Hilliard (2002)
Antibody cross-reactivity of alphaherpesviruses as mirrored in naturally infected primates
Archives of Virology, 147
B. Bryan, C. Espana, R. Emmons, N. Vijayan, P. Hoeprich (1975)
Recovery from encephalomyelitis caused by Herpesvirus simiae. Report of a case.
Archives of internal medicine, 135 6
J. Wertheim, Martin Smith, Davey Smith, K. Scheffler, Sergei Pond (2014)
Evolutionary Origins of Human Herpes Simplex Viruses 1 and 2
Molecular Biology and Evolution, 31
E. Boulter, H. Zwartouw, B. Thornton (1981)
Postexposure immunoprophylaxis against B virus (Herpesvirus simiae) infection.
British Medical Journal (Clinical research ed.), 283
Qing Lin, Gailing Yuan, L. Ai, Juan Li, Hai-Long Li (2012)
Seroprevalence of BV (Macacine herpesvirus 1) in bred cynomolgus monkeys in Cambodia.
The Journal of veterinary medical science, 74 3
S. Tyler, A. Severini (2006)
The Complete Genome Sequence of Herpesvirus Papio 2 (Cercopithecine Herpesvirus 16) Shows Evidence of Recombination Events among Various Progenitor Herpesviruses
Journal of Virology, 80
S. Nii (1972)
Abortive infection of LLC-MK2 cells by Herpes simplex virus.
Biken journal, 15 1
O. Deimlingi, Jiri Forejt, T. Wienker (1988)
Allelic profile at 37 biochemical loci of two inbred strains of the house mouse derived from wild Mus musculus musculus
Laboratory Animals, 22
E. Boulter (1975)
The isolation of monkey B virus (Herpesvirus simiae) from the trigeminal ganglia of a healthy seropositive rhesus monkey.
Journal of biological standardization, 3 3
J. Chou, E. Kern, R. Whitley, B. Roizman (1990)
Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture.
Science, 250 4985
M. Kessler, J. Hilliard (1990)
Seroprevalence of B virus (Herpesvirus simiae) antibodies in a naturally formed group of rhesus macaques.
Journal of medical primatology, 19 2
L. Perelygina, I. Patrusheva, Soumya Hombaiah, H. Zurkuhlen, Martin Wildes, N. Patrushev, J. Hilliard (2005)
Production of Herpes B Virus Recombinant Glycoproteins and Evaluation of Their Diagnostic Potential
Journal of Clinical Microbiology, 43
J. Conner, J. Macfarlane, H. Lankinen, H. Marsden (1992)
The unique N terminus of the herpes simplex virus type 1 large subunit is not required for ribonucleotide reductase activity.
The Journal of general virology, 73 ( Pt 1)
Jennifer Huff, R. Eberle, J. Capitanio, S. Zhou, P. Barry, P. Barry (2003)
Differential detection of B virus and rhesus cytomegalovirus in rhesus macaques.
The Journal of general virology, 84 Pt 1
Mugdha Vasireddi, J. Hilliard (2012)
Herpes B Virus, Macacine Herpesvirus 1, Breaks Simplex Virus Tradition via Major Histocompatibility Complex Class I Expression in Cells from Human and Macaque Hosts
Journal of Virology, 86
E. Boulter, D. Grant (1977)
Latent infection of monkeys with B virus and prophylactic studies in a rabbit model of this disease.
The Journal of antimicrobial chemotherapy, 3 Suppl A
Y. Minamishima, Y. Eizuru (1977)
Susceptibility of Primate Diploid Cells to Human Herpesviruses
Microbiology and Immunology, 21
Weigler Bj (1992)
Biology of B Virus in Macaque and Human Hosts: A Review
Clinical Infectious Diseases, 14
S. Keeble, G. Christofinis, W. Wood (1958)
Natural virus-B infection in rhesus monkeys.
The Journal of pathology and bacteriology, 76 1
David Davenport, David Johnson, Gary Holmes, Jewett Da, Stephen Ross, Julia Hilliard (1994)
Diagnosis and management of human B virus (Herpesvirus simiae) infections in Michigan.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 19 1
A. Vizoso (1975)
Recovery of herpes simiae (B virus) from both primary and latent infections in rhesus monkeys.
British journal of experimental pathology, 56 6
B. Roizman (1974)
The Herpesviruses. Albert S. Kaplan, Ed. Academic Press, New York, 1973. xvi, 740 pp., illus. $31
Science, 184
A. Artenstein, C. Hicks, Brad Goodwin, J. Hilliard (1991)
Human infection with B virus following a needlestick injury.
Reviews of infectious diseases, 13 2
Richard Eberle, J. Hilliard (1989)
Serological evidence for variation in the incidence of herpesvirus infections in different species of apes
Journal of Clinical Microbiology, 27
W. Johnston, Jesson Yeh, R. Nierenberg, Gabrielle Procopio (2015)
Exposure to Macaque Monkey Bite.
The Journal of emergency medicine, 49 5
E. Weir, P. Bhatt, R. Jacoby, J. Hilliard, S. Morgenstern (1993)
Infrequent shedding and transmission of herpesvirus simiae from seropositive macaques.
Laboratory animal science, 43 6
J. Hilliard, D. Black, Richard Eberle (2005)
Simian alphaherpesviruses and their relation to the human herpes simplex viruses
Archives of Virology, 109
A. Sabin, A. Wright (1934)
ACUTE ASCENDING MYELITIS FOLLOWING A MONKEY BITE, WITH THE ISOLATION OF A VIRUS CAPABLE OF REPRODUCING THE DISEASE
The Journal of Experimental Medicine, 59
Zhe Huang, Su-qin Wu, Yaoji Liang, Xiaojuan Zhou, Wanze Chen, Lisheng Li, Jianfeng Wu, Q. Zhuang, Chang’an Chen, Jingxian Li, Chuan-Qi Zhong, Weixiang Xia, Rongbin Zhou, C. Zheng, Jiahuai Han (2015)
RIP1/RIP3 binding to HSV-1 ICP6 initiates necroptosis to restrict virus propagation in mice.
Cell host & microbe, 17 2
C. Carlson, M. O’Sullivan, M. Jayo, D. Anderson, E. Harber, W. Jerome, B. Bullock, R. Heberling (1997)
Fatal Disseminated Cercopithecine Herpesvirus 1 (Herpes B) Infection in Cynomolgus Monkeys {Macaca fascicularis)
Veterinary Pathology, 34
L. Jones-Engel, G. Engel, M. Schillaci, A. Rompis, A. Putra, K. Suaryana, A. Fuentes, B. Beer, S. Hicks, R. White, B. Wilson, J. Allan (2005)
Primate-to-Human Retroviral Transmission in Asia
Emerging Infectious Diseases, 11
K. Rogers, R. Wolf, G. White, R. Eberle (2005)
Experimental infection of baboons (Papio cynocephalus anubis) with apathogenic and neurovirulent subtypes of herpesvirus papio 2.
Comparative medicine, 55 5
D. Katz, W. Shi, P. Krug, J. Hilliard (2002)
Alphaherpesvirus antigen quantitation to optimize the diagnosis of herpes B virus infection.
Journal of virological methods, 103 1
Xing Wang, Yun Li, Shan Liu, Xiaoliang Yu, Lin Li, Cuilin Shi, Wenhui He, Jun Li, Lei Xu, Zhilin Hu, Lu Yu, Zhong Yang, Qin Chen, Lin Ge, Zili Zhang, Biqi Zhou, Xuejun Jiang, She Chen, S. He (2014)
Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense
Proceedings of the National Academy of Sciences, 111
T. Kramer, L. Enquist (2013)
Directional Spread of Alphaherpesviruses in the Nervous System
Viruses, 5
R. Giacomo, K. Shah (1972)
Virtual absence of infection with Herpesvirus simiae in colony-reared rhesus monkeys (Macaca mulatta), with a literature review on antibody prevalence in natural and laboratory rhesus populations.
Laboratory animal science, 22 1
Y. Ueda, I. Tagaya, K. Shiroki (2005)
Immunological relationship between herpes simplex virus and B virus
Archiv für die gesamte Virusforschung, 24
Orcutt Rp, Pucak Gj, Foster Hl, Kilcourse Jt, T. Ferrell (1976)
Multiple testing for the detection of B virus antibody in specially handled rhesus monkeys after capture from virgin trapping grounds.
Laboratory animal science, 26 1
A. Freifeld, J. Hilliard, J. Hilliard, J. Southers, J. Southers, J. Southers, M. Murray, M. Murray, M. Murray, B. Savarese, B. Savarese, B. Savarese, J. Schmitt, J. Schmitt, S. Straus, S. Straus (1995)
A controlled seroprevalence survey of primate handlers for evidence of asymptomatic herpes B virus infection.
The Journal of infectious diseases, 171 4
T. Todo (2012)
Active immunotherapy: oncolytic virus therapy using HSV-1.
Advances in experimental medicine and biology, 746
D. Black, K. Ohsawa, S. Tyler, L. Maxwell, Richard Eberle (2014)
A single viral gene determines lethal cross-species neurovirulence of baboon herpesvirus HVP2.
Virology, 452-453
E. Blewett, J. Saliki, R. Eberle (1999)
Development of a competitive ELISA for detection of primates infected with monkey B virus (Herpesvirus simiae).
Journal of virological methods, 77 1
R. Moutier, M. Carlier (1991)
Mandible shape analysis in Y-congenic strains of mice
Laboratory Animals, 25
R. Eberle, J. Hilliard (1995)
The simian herpesviruses.
Infectious agents and disease, 4 2
F. Mitsunaga, Shin Nakamura, T. Hayashi, R. Eberle (2007)
Changes in the titer of anti-B virus antibody in captive macaques (Macaca fuscata, M. mulatta, M. fascicularis).
Comparative medicine, 57 1
K. Tanabayashi, R. Mukai, A. Yamada (2001)
Detection of B Virus Antibody in Monkey Sera Using Glycoprotein D Expressed in Mammalian Cells
Journal of Clinical Microbiology, 39
Joany Chou, J. Chen, M. Gross, B. Roizman (1995)
Association of a M(r) 90,000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2 alpha and premature shutoff of protein synthesis after infection with gamma 134.5- mutants of herpes simplex virus 1.
Proceedings of the National Academy of Sciences of the United States of America, 92 23
B. Weigler (1992)
Biology of B virus in macaque and human hosts: a review.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 14 2
M. Andrade, J. Yee, P. Barry, A. Spinner, J. Roberts, P. Cabello, J. Leite, N. Lerche (2003)
Prevalence of antibodies to selected viruses in a long‐term closed breeding colony of rhesus macaques (Macaca mulatta) in Brazil
American Journal of Primatology, 59
L. Mease, Katheryn Baker (2012)
Monkey Bites among US Military Members, Afghanistan, 2011
Emerging Infectious Diseases, 18
G. Holmes, J. Hilliard, K. Klontz, A. Rupert, C. Schindler, E. Parrish, D. Griffin, G. Ward, N. Bernstein, Terrell Bean, Michael Ball, J. Brady, Michael Wilder, J. Kaplan (1990)
B virus (Herpesvirus simiae) infection in humans: epidemiologic investigation of a cluster.
Annals of internal medicine, 112 11
M. Huffman (2000)
The sacred monkeys of Bali
Primates, 41
M. Daniel, F. García, L. Meléndez, R. Hunt, J. O'Connor, D. Silva (1975)
Multiple Herpesvirus simiae isolation from a rhesus monkey which died of cerebral infarction.
Laboratory animal science, 25 3
M. Holden (1934)
Herpes Encephalitis Problem, II
Journal of Nervous and Mental Disease, 79
A. Simmons, A. Nash (1984)
Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease
Journal of Virology, 52
Lauren Brush, D. Black, Kimberly McCormack, L. Maxwell, G. Wright, J. Ritchey, M. Payton, R. Eberle (2014)
Papiine herpesvirus 2 as a predictive model for drug sensitivity of Macacine herpesvirus 1 (monkey B virus).
Comparative medicine, 64 5
J. Ritchey, Mark Payton, Richard Eberle (2005)
Clinicopathological characterization of monkey B virus (Cercopithecine herpesvirus 1) infection in mice.
Journal of comparative pathology, 132 2-3
G. Chellman, V. Lukas, E. Eugui, K. Altera, S. Almquist, J. Hilliard (1992)
Activation of B virus (Herpesvirus simiae) in chronically immunosuppressed cynomolgus monkeys.
Laboratory animal science, 42 2
J. D. Pimentel (2008)
Herpes B virus --
Canadian Medical Association Journal, J. D. Pimentel, “Herpes B virus -- "B" is for Brebner: Dr. William Bartlet Brebner (1903-1932),” Canadian Medical Association Journal, vol. 178, no. 6, pp. 734–734, 2008. View at Publisher · View at Google Scholar
G. Engel, L. Jones-Engel, M. Schillaci, K. Suaryana, A. Putra, A. Fuentes, R. Henkel (2002)
Human Exposure to Herpesvirus B–Seropositive Macaques, Bali, Indonesia
Emerging Infectious Diseases, 8
D. Anderson, R. Swenson, J. Orkin, S. Kalter, H. McClure (1994)
Primary Herpesvirus simiae (B-virus) infection in infant macaques.
Laboratory animal science, 44 5
D. Black, J. Ritchey, M. Payton, R. Eberle (2014)
Role of the virion host shutoff protein in neurovirulence of monkey B virus (Macacine herpesvirus 1)
Virologica Sinica, 29
L. Cropper, D. Lees, R. Patt, I. Sharp, D. Brown (2005)
Monoclonal antibodies for the identification of herpesvirus simiae (B virus)
Archives of Virology, 123
Weigler Bj, Jeffrey Roberts, David Hird, Nicholas Lerche, Julia Hilliard (1990)
A cross sectional survey for B virus antibody in a colony of group housed rhesus macaques.
Laboratory animal science, 40 3
S. Keeble (1960)
B VIRUS INFECTION IN MONKEYS
Annals of the New York Academy of Sciences, 85
Alberto Severini, Alberto Severini, S. Tyler, G. Peters, D. Black, Richard Eberle (2013)
Genome sequence of a chimpanzee herpesvirus and its relation to other primate alphaherpesviruses
Archives of Virology, 158
I. Patrusheva, L. Perelygina, I. Torshin, Julia Lecher, J. Hilliard (2016)
B Virus (Macacine Herpesvirus 1) Divergence: Variations in Glycoprotein D from Clinical and Laboratory Isolates Diversify Virus Entry Strategies
Journal of Virology, 90
F. Nagler, M. Klotz (1958)
A fatal B virus infection in a person subject to recurrent herpes labialis.
Canadian Medical Association journal, 79 9
L. Jones-Engel, G. Engel, J. Heidrich, M. Chalise, N. Poudel, R. Viscidi, P. Barry, J. Allan, R. Grant, Randy Kyes (2006)
Temple Monkeys and Health Implications of Commensalism, Kathmandu, Nepal
Emerging Infectious Diseases, 12
S. Efstathiou, C. Preston (2005)
Towards an understanding of the molecular basis of herpes simplex virus latency.
Virus research, 111 2
G. Gosztonyi, D. Falke, H. Ludwig (1992)
Axonal-transsynaptic spread as the basic pathogenetic mechanism in B virus infection of the nervous system.
Journal of medical primatology, 21 1
Chris Boutell, R. Everett (2013)
Regulation of alphaherpesvirus infections by the ICP0 family of proteins.
The Journal of general virology, 94 Pt 3
Charles Calvo, S. Friedlander, J. Hilliard, R. Swarts, J. Nielsen, H. Dhindsa, R. Welch, R. Dix (2011)
Case Report: Reactivation Of Latent B Virus (Macacine Herpesvirus 1) Presenting As Bilateral Uveitis, Retinal Vasculitis And Necrotizing Herpetic Retinitis
Investigative Ophthalmology & Visual Science, 52
G. Breen, S. Lamb, A. Otaki (1958)
Monkey-bite Encephalomyelitis
British Medical Journal, 2
B. Roizman, R. Whitley (2013)
An inquiry into the molecular basis of HSV latency and reactivation.
Annual review of microbiology, 67
R. Eberle (1992)
Evidence for an alpha-herpesvirus indigenous to mountain gorillas.
Journal of medical primatology, 21 5
R. Eberle, L. Maxwell, S. Nicholson, D. Black, L. Jones-Engel (2017)
Genome sequence variation among isolates of monkey B virus (Macacine alphaherpesvirus 1) from captive macaques.
Virology, 508
J. Pimentel (2008)
Herpes B virus — “B” is for Brebner: Dr. William Bartlet Brebner (1903–1932)
Canadian Medical Association Journal, 178
K. Rogers, D. Black, R. Eberle (2006)
Primary mouse dermal fibroblast cell cultures as an in vitro model system for the differential pathogenicity of cross-species herpesvirus papio 2 infections
Archives of Virology, 152
G. Gosztonyi, D. Falke, H. Ludwig (1992)
Axonal and transsynaptic (transneuronal) spread of Herpesvirus simiae (B virus) in experimentally infected mice.
Histology and histopathology, 7 1
K. Ohsawa, D. Black, Hiroshi Sato, K. Rogers, R. Eberle (2003)
Sequence and genetic arrangement of the UL region of the monkey B virus (Cercopithecine herpesvirus 1) genome and comparison with the UL region of other primate herpesviruses
Archives of Virology, 148
L. Perelygina, I. Patrusheva, Mugdha Vasireddi, N. Brock, J. Hilliard (2015)
B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells
Journal of Virology, 89
B. Troan, L. Perelygina, I. Patrusheva, A. Wettere, J. Hilliard, M. Loomis, Ryan Voe (2007)
Naturally transmitted herpesvirus papio-2 infection in a black and white colobus monkey.
Journal of the American Veterinary Medical Association, 231 12
D. Lembo, W. Brune (2009)
Tinkering with a viral ribonucleotide reductase.
Trends in biochemical sciences, 34 1
R. Hull, J. Nash (1960)
Immunization against B virus infection. I. Preparation of an experimental vaccine.
American journal of hygiene, 71
H. Zwartouw, E. Boulter (1984)
Excretion of B virus in monkeys and evidence of genital infection
Laboratory Animals, 18
(1999)
Molecular aspects of monkey B virus and implications for diagnostic test development
(1987)
Herpesvirus simiae: historical perspective
Meredith Simon, M. Daniel, David Lee-Parritz, N. King, D. Ringler (1993)
Disseminated B virus infection in a cynomolgus monkey.
Laboratory animal science, 43 6
N. Riesland, H. Wilde (2015)
Expert Review of Evidence Bases for Managing Monkey Bites in Travelers.
Journal of travel medicine, 22 4
F. P. Gay and M. Holden (1933)
The herpes encephalitis problem, ii,
The Journal of Infectious Diseases, F. P. Gay and M. Holden, “The herpes encephalitis problem, ii,” The Journal of Infectious Diseases, vol. 53, no. 3, pp. 287–303, 1933. View at Publisher · View at Google Scholar · View at Scopus
K. Hummeler, W. Davidson, W. Henle, A. Laboccetta, H. Ruch (1959)
Encephalomyelitis due to infection with Herpesvirus simiae (herpes B virus); a report of two fatal, laboratory-acquired cases.
The New England journal of medicine, 261 2
L. Perelygina, H. Zurkuhlen, I. Patrusheva, J. Hilliard (2002)
Identification of a herpes B virus-specific glycoprotein d immunodominant epitope recognized by natural and foreign hosts.
The Journal of infectious diseases, 186 4
G. Engel, Christopher Small, Khanh Soliven, M. Feeroz, Xiaoxing Wang, M. Hasan, Gunwha Oh, S. Alam, Karen Craig, Dana Jackson, Frederick A, Matsen Iv, M. Linial, L. Jones-Engel (2013)
Zoonotic simian foamy virus in Bangladesh reflects diverse patterns of transmission and co-infection
Emerging Microbes & Infections, 2
H. Zwartouw, J. Macarthur, E. Boulter, J. Seamer, J. Marston, Arnold Chamove (1984)
Transmission of B virus infection between monkeys especially in relation to breeding colonies
Laboratory Animals, 18
B. Roizman, Guoying Zhou, Te Du (2011)
Checkpoints in productive and latent infections with herpes simplex virus 1: conceptualization of the issues
Journal of NeuroVirology, 17
Boulter Ea, Kalter Ss, Heberling Rl, Guajardo Je, Lester Tl (1982)
A comparison of neutralization tests for the detection of antibodies to Herpesvirus simiae (monkey B virus).
Laboratory animal science, 32 2
H. Huemer, C. Wechselberger, A. Bennett, D. Falke, L. Harrington (2003)
Cloning and expression of the complement receptor glycoprotein C from Herpesvirus simiae (herpes B virus): protection from complement-mediated cell lysis.
The Journal of general virology, 84 Pt 5
B. He, M. Gross, B. Roizman (1997)
The γ134.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1α to dephosphorylate the α subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase
Proceedings of the National Academy of Sciences of the United States of America, 94
A. Arvin, G. Campadelli-Fiume, E. Mocarski, P. Moore, B. Roizman, R. Whitley, K. Yamanishi (2007)
Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis
(1986)
Comparison of the primate alphaherpesviruses - I. Characterization of two Herpesviruses from spider monkeys and squirrel monkeys and viral polypeptides synthesized in infected cells
R. Whitley, J. Gnann (2002)
Viral encephalitis: familiar infections and emerging pathogens
The Lancet, 359
Mugdha Vasireddi, J. Hilliard (2017)
Regulation of PI3K/Akt dependent apoptotic markers during b virus infection of human and macaque fibroblasts
PLoS ONE, 12
L. Perelygina, I. Patrusheva, H. Zurkuhlen, J. Hilliard (2002)
Characterization of B virus glycoprotein antibodies induced by DNA immunization
Archives of Virology, 147
C Bolovan, N. Sawtell, R. Thompson (1994)
ICP34.5 mutants of herpes simplex virus type 1 strain 17syn+ are attenuated for neurovirulence in mice and for replication in confluent primary mouse embryo cell cultures
Journal of Virology, 68
Autumn Smith, D. Black, R. Eberle (1998)
Molecular Evidence for Distinct Genotypes of Monkey B Virus (Herpesvirus Simiae) Which Are Related to the Macaque Host Species
Journal of Virology, 72
D. Katz, W. Shi, M. Gowda, Mugdha Vasireddi, I. Patrusheva, H. Seoh, Chadi Filfili, Martin Wildes, J. Oh, J. Hilliard (2017)
Identification of unique B virus (Macacine Herpesvirus 1) epitopes of zoonotic and macaque isolates using monoclonal antibodies
PLoS ONE, 12
B. Roizman, N. Markovitz (1997)
Herpes simplex virus virulence: the functions of the gamma (1)34.5 gene.
Journal of neurovirology, 3 Suppl 1
Richard Whitley, Earl Kern, S. Chatterjee, Joany Chou, Bernard Roizmant (1993)
Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models.
The Journal of clinical investigation, 91 6
Lingfu Li, Zhengliang Qiu, Yan Li, F. Liang, Huahu Ye, Yongqin Cai, Wan-feng Guo, Yan Li, Junjie Yue (2014)
Herpes B virus gD interaction with its human receptor – an in silico analysis approach
Theoretical Biology & Medical Modelling, 11
Xianghong Jing, Melissa Cerveny, Kui Yang, B. He (2004)
Replication of Herpes Simplex Virus 1 Depends on the γ134.5 Functions That Facilitate Virus Response to Interferon and Egress in the Different Stages of Productive Infection
Journal of Virology, 78
J. Chou, JANE-JANE CHENt, M. GROSSt, B. Roizman (2005)
Association of a Mr 90,000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2a and premature shutoff of protein synthesis after infection with y134.5- mutants of herpes simplex virus 1
F. Lee, Y.-J. Lin, M. Deng, T-Y Lee, C.-C. Huang (2007)
Prevalence of antibody reaction with cercopithecine herpesvirus 1 antigen in Macaca cyclopis, Macaca fascicularis, and Papio anubis in Taiwan
Journal of Medical Primatology, 36
K. Ohsawa, D. Black, R. Torii, Hiroshi Sato, R. Eberle (2002)
Detection of a unique genotype of monkey B virus (Cercopithecine herpesvirus 1) indigenous to native Japanese macaques (Macaca fuscata).
Comparative medicine, 52 6
Van Gl, Melnick Jl (1961)
Neutralizing antibodies in human sera to Herpesvirus simiae (B virus).
Texas reports on biology and medicine, 19
Qing Fan, Melanie Amen, Mallory Harden, A. Severini, A. Griffiths, R. Longnecker (2012)
Herpes B Virus Utilizes Human Nectin-1 but Not HVEM or PILRα for Cell-Cell Fusion and Virus Entry
Journal of Virology, 86
Jennifer Huff, P. Barry (2003)
B-Virus (Cercopithecine herpesvirus 1) Infection in Humans and Macaques: Potential for Zoonotic Disease
Emerging Infectious Diseases, 9
Richard Eberle, D. Black, J. Hilliard (2005)
Relatedness of glycoproteins expressed on the surface of simian herpesvirus virions and infected cells to specific HSV glycoproteins
Archives of Virology, 109
Hongyan Guo, S. Omoto, P. Harris, J. Finger, J. Bertin, P. Gough, W. Kaiser, E. Mocarski (2015)
Herpes simplex virus suppresses necroptosis in human cells.
Cell host & microbe, 17 2
R. Henkel, H. McClure, P. Krug, D. Katz, J. Hilliard (2002)
Serological evidence of alpha herpesvirus infection in sooty mangabeys
Journal of Medical Primatology, 31
R. Heberling, S. Kalter (1987)
A dot-immunobinding assay on nitrocellulose with psoralen inactivated Herpesvirus simiae (B virus).
Laboratory animal science, 37 3
M. Slomka, L. Harrington, C. Arnold, J. Norcott, D. Brown (1995)
Complete nucleotide sequence of the herpesvirus simiae glycoprotein G gene and its expression as an immunogenic fusion protein in bacteria.
The Journal of general virology, 76 ( Pt 9)
D. Katz, J. Hilliard, R. Eberle, S. Lipper (1986)
ELISA for detection of group-common and virus-specific antibodies in human and simian sera induced by herpes simplex and related simian viruses.
Journal of virological methods, 14 2
Michael Besecker, Mallory Harden, Guanglin Li, Xiu-Jie Wang, A. Griffiths (2009)
Discovery of Herpes B Virus-Encoded MicroRNAs
Journal of Virology, 83
Wallace Davidson, K. Hummeler (1960)
B VIRUS INFECTION IN MAN
Annals of the New York Academy of Sciences, 85
Cahiers / Santé , Infection humaine par le virus B du singe en Afrique
(2001)
Cercopithecine herpesvirus (B virus)
(1998)
Fatal Cercopithecine herpesvirus 1 (B virus) infection following a mucocutaneous exposure and interim recommendations for worker protection.
MMWR. Morbidity and mortality weekly report, 47 49
L. Lee, P. Schaffer (1998)
A Virus with a Mutation in the ICP4-Binding Site in the L/ST Promoter of Herpes Simplex Virus Type 1, but Not a Virus with a Mutation in Open Reading Frame P, Exhibits Cell-Type-Specific Expression of γ134.5 Transcripts and Latency-Associated Transcripts
Journal of Virology, 72
E. Blewett, D. Black, R. Eberle (1996)
Characterization of virus-specific and cross-reactive monoclonal antibodies to Herpesvirus simiae (B virus).
The Journal of general virology, 77 ( Pt 11)
B. Roizman, B. Roizman, M. Stinski (1983)
The Herpesviruses
J. Hilliard, R. Eberle, S. Lipper, R. Muñoz, S. Weiss (2005)
Herpesvirus simiae (B virus): Replication of the virus and identification of viral polypeptides in infected cells
Archives of Virology, 93
Yael Tsalenchuck, T. Tzur, I. Steiner, A. Panet (2014)
Different modes of herpes simplex virus type 1 spread in brain and skin tissues
Journal of NeuroVirology, 20
A. Fuentes, Scott Gamerl (2005)
Disproportionate participation by age/sex classes in aggressive interactions between long‐tailed macaques (Macaca fascicularis) and human tourists at Padangtegal monkey forest, Bali, Indonesia
American Journal of Primatology, 66
W. Blyth, D. Harbour, T. Hill (1984)
Pathogenesis of zosteriform spread of herpes simplex virus in the mouse.
The Journal of general virology, 65 ( Pt 9)
M. Yamada (1983)
Replication of herpes simplex virus in two cell systems derived from rhesus monkeys.
Biken journal, 26 1
K. Rogers, J. Ritchey, M. Payton, D. Black, R. Eberle (2006)
Neuropathogenesis of herpesvirus papio 2 in mice parallels infection with Cercopithecine herpesvirus 1 (B virus) in humans.
The Journal of general virology, 87 Pt 2
K. Rogers, K. Ealey, J. Ritchey, D. Black, R. Eberle (2003)
Pathogenicity of Different Baboon Herpesvirus Papio 2 Isolates Is Characterized by either Extreme Neurovirulence or Complete Apathogenicity
Journal of Virology, 77

Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2018 R. Eberle and L. Jones-Engel. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8639
eISSN: 1687-8647
DOI: 10.1155/2018/5248420
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Abstract

Hindawi Advances in Virology Volume 2018, Article ID 5248420, 17 pages https://doi.org/10.1155/2018/5248420 Review Article Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1) 1 2 R. Eberle and L. Jones-Engel Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater,OK74078,USA Department of Anthropology and Center for Studies in Ecology and Demography, University of Washington, Seattle, WA 98195, USA Correspondence should be addressed to R. Eberle; r.eberle@okstate.edu Received 10 October 2017; Accepted 10 January 2018; Published 13 February 2018 Academic Editor: Anuj Sharma Copyright © 2018 R. Eberle and L. Jones-Engel. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Monkey B virus (Macacine alphaherpesvirus 1; BV) occurs naturally in macaques of the genus Macaca, which includes rhesus and long-tailed (cynomolgus) monkeys that are widely used in biomedical research. BV is closely related to the human herpes simplex viruses (HSV), and BV infections in its natural macaque host are quite similar to HSV infections in humans. Zoonotic BV is extremely rare, having been diagnosed in only a handful of North American facilities with the last documented case occurring in 1998. However, BV is notorious for its neurovirulence since zoonotic infections are serious, usually involving the central nervous system, and are frequently fatal. Little is known about factors underlying the extreme neurovirulence of BV in humans. Here we review what is actually known about the molecular biology of BV and viral factors aec ff ting its neurovirulence. Based on what is known about related herpesviruses, areas for future research that may elucidate mechanisms underlying the neurovirulence of this intriguing virus are also reviewed. 1. Introduction zoonotic BV infection following exposure to macaques has a mortality rate of∼80%. Here we review what is known about Herpesviruses are ubiquitous viruses, found in a wide variety this relatively neglected virus with regard to its infamous of species including mammals, birds, and reptiles. Three neurovirulence. subfamilies of the Herpesviridae family (Alpha-, Beta- and Gammaherpesvirinae) are found in the order Primates. Of 2. BV in Its Natural Host these, alphaherpesviruses typically infect and remain within theperipheralsensorynervoussystemforthelifeoftheirhost Monkey B virus (BV) occurs naturally in all 17 species as part of their natural life cycle. The close and prolonged of macaque monkeys that comprise the genus Macaca. association of these viruses with their host over its entire Macaques are ecologically adaptable monkeys and are the lifetime with only rare impairment of nervous system func- most numerous and widely distributed nonhuman primate tion implies an exquisite degree of host-virus coadaptation. ontheplanet.em Th ajorityofmacaquespeciesaredistributed On occasion stability of this commensal symbiotic host-virus throughout Asia and their ubiquity has led to three of these relationship can be altered, resulting in severe or even fatal species (M. mulatta, M. fascicularis, and M. nemestrina)being diseaseoeft ninvolving thecentral nervoussystem(CNS). used as biomedical research models for nearly a century [1– In cases where an alphaherpesvirus infects a host of another 4]. Although known by several names over the years since species, the result can be, but is not always, catastrophic. eTh its initial isolation in 1932 (Herpesvirus simiae, monkey B most notorious example of this is monkey B virus (Macacine virus, Herpes B, and Cercopithecine herpesvirus 1), BV is alphaherpesvirus 1; BV), an alphaherpesvirus enzootic in currently designated as Macacine alphaherpesvirus 1bythe macaques of the genus Macaca.Though exceptionallyrare, International Committee on Taxonomy of Viruses. 2 Advances in Virology From a biological standpoint, in macaques BV is very 3. Zoonotic BV Infection much like herpes simplex virus (HSV) in humans. Both In 1932 a young physician, William Brebner, performing HSV and BV are normally transmitted horizontally via direct poliovirus research with rhesus macaques was bitten on the contact and exchange of bodily secretions [3, 5–7]. eTh finger [40–42]. He developed herpetic-like lesions on the prevalence of BV in macaques is related to age, increasing finger, and the infection eventually progressed to involve the progressively from infant to adult [8–17]. eTh re are very CNS. The patient died several weeks later from an acute few studies on the prevalence or transmission of BV in ascending myeloencephalitis. A herpesvirus was isolated free-ranging populations. In captive macaque colonies, very from several tissues at autopsy. Although initially identified young monkeys (<2 yr of age) usually acquire BV as an as HSV, the virus was subsequently shown to be distinct from oral infection, while in socially and reproductively mature HSV and was designated as “the B virus” [40, 42]. macaques primary BV infections are usually genital. eTh While the exact number is not available, less than 60 prevalence of BV in adults of both wild populations and additional cases of pathogenic zoonotic BV infection have captive breeding colonies typically ranges from 70% to nearly occurred sporadically over the last 85 years, all resulting 100%. Only rarely does BV cause lethal infections in healthy from exposure to laboratory or captive macaques or macaque macaques, just as HSV rarely causes encephalitis or other tissues [2,4,5,43–50]. WhilezoonoticBVinfectionsare serious disease in humans [18]. exceedingly rare, the fatality rate is 70–80% and many survivors are left with deteriorative neurologic sequelae. eTh As with HSV in humans, most primary BV infections majority of exposures have been associated with bites or occur in mucosal epithelium and do not usually produce scratches from captive, laboratory-housed macaques. How- overt clinical signs, although lesions are sometimes visible ever, additional modes of exposure have been implicated on close inspection [27]. As the virus replicates in epithelial including mucosal membrane contact with macaque urine cells, sufficient levels of infectious virus accumulate allowing and/or feces, needlestick injury, and contamination of cuts the virus to invade unmyelinated sensory nerve endings with material from primary macaque cells in the labora- present in the epidermis. Once in sensory neurons, the tory [43, 44, 48]. With the sole exception of one spousal virus establishes a latent infection in the sensory ganglion, person-to-person infection [47], all zoonotic BV infections where the viral genome is retained in the nuclei of neurons have involved primate veterinarians, animal care personnel, without entering the lytic viral replicative cycle that occurs in or laboratory researchers in North America working with epithelial cells [6, 28–30]. Viral replication in epithelial tissue macaques or macaque biologics. BV is the single most serious is eventually controlled and the virus is eliminated by the occupational zoonotic concern for persons working with or host adaptive immune response. eTh only indication that a around macaques. monkey continues to harbor BV is the presence of circulating While the clinical course of zoonotic BV infections can antiviralIgG.Ithasbeen shownincaptive macaquesthat,in vary,initial symptomsusuallydevelop within1–3weeks ofan rare instances, usually in infants or the very young, primary exposure incident [51]. The nature of initial clinical symptoms infections may not end with the establishment of latency, also varies but usually includes nonspecific u-li fl ke symp- but rather progress as generalized infections that spread toms, vesicular herpetic lesions at the site of exposure, and throughout the body and are frequently fatal [31–34]. symptoms indicative of involvement of the peripheral and/or As is typical of other alphaherpesviruses, BV can period- central nervous systems. The infection progressively spreads ically reactivate from the latent state in response to various along sensory nerves into the spinal cord and ascends into the stressful stimuli, resulting in shedding of infectious virus. brainstem. Typically, the destruction of nervous tissue as the While lesions may be apparent, most recurrences do not virus spreads within the CNS results in encephalomyelitis and produce clinically apparent lesions; rather, infectious virus is respiratory failure in terminal stages of the infection. Once theCNS isinvolved,thefinaloutcomeisalmostinvariably shed asymptomatically. Like HSV in humans, the frequency death. of BV shedding appears to be fairly low (2-3%) [35–37]. Stress related to social/housing challenges, transportation, oTh ughmostpersonsknowntobeinfectedwithBVdie, immunosuppression, and seasonal breeding have all been some do survive and some survivors can periodically shed linked to reactivation of latent BV [6, 7, 38, 39]. virusaeft rrecovery[46,52–54].Severalcases of zoonotic BV have also occurred in persons who have a history of In many ways, BV is the macaque equivalent of human working with macaques but without any known BV exposure HSV: BV and its macaque hosts have coevolved, resulting immediately prior to the appearance of clinical signs. Both in an exquisitely fine-tuned interaction with one another of these observations suggest that BV latency not only that results in perpetuation of the virus within the host’s occurs in humans, but that reactivation of latent BV can be nervous system with minimal adverse eeff cts on the host but associated with clinical disease [47, 54, 55]. Since primary also with occasional shedding of infectious virus that can be BV and HSV infections in the natural host species are usually transmitted to a na¨ıve host, thereby ensuring perpetuation asymptomatic, the potential exists for asymptomatic zoonotic of the virus. eTh notorious neurovirulence of BV is therefore BV infections to occur as well. However, there has only been not evident in its natural macaque hosts; the neurovirulence one study that tested persons working with captive macaques of BV only becomes apparent when BV infects other species, for serological evidence of BV infection [56]. None were particularly humans. Advances in Virology 3 detected, suggesting that asymptomatic infections are likely macaque contact and injury [19]. If such persons had experi- uncommon, if they do occur. enced BV infection over their years in close contact with wild macaques, their antiviral serum antibodies should differ in A puzzling aspect of zoonotic BV infections is the notable their virus-specificity from that of persons never exposed to lack of any fatal or even clinically evident BV infections in BV. When an HSV infected person is infected with an anti- Asia where BV-positive macaques and humans have copious genically related virus, an anamnestic response will occur to close interactions, and exposure to macaque bodily uids fl antigens shared by the two viruses, while a de novo response through bites, scratches, and mucosal splashes is common [11, will occur to antigens specific to the second virus. us, Th 19, 57–59]. The human-macaque interface is diverse and deep detection of BV-specific antibodies is a difficult problem, in Asia, in part because of cultural and religious beliefs that astheBV-specica fi ntibodyresponsedevelopsmoreslowly provide a context for tolerance and a measure of protection andmaybe overshadowed by theimmediateandstrong for these ubiquitous monkeys. Macaques, particularly the response to cross-reactive antigens. Consequently, persons abundant rhesus, long-tailed and pigtail monkeys, are found infected with HSV who had experienced an asymptomatic at the thousands of temples and shrines located throughout BV infection would be expected to have higher levels of a broad geographic swath extending east from Afghanistan antibodies directed against antigens shared by all primate to Japan and south through the Indonesian archipelago. alphaherpesviruses than would be present in sera of persons Millions ofpeople wholiveandwork atthesesites,aswell only infected with HSV. as those who worship, have frequent contact with macaques. Additionally, many of these sacred sites are also international Limited testing compared the relative reactivity of sera tourist destinations, drawing hundreds of thousands of vis- from persons working in monkey forests with that of persons itors each year who come to appreciate the culture and to having no known contact with monkeys (negative controls) feed and interact with the monkeys. Human exposures are and patients that died of zoonotic BV infection (positive routine, with macaques aggressively pursuing food handouts controls) (Figure 1). When sera were tested by ELISA against whileclimbingonvisitors. Bitesand scratchescommonly HSV and multiple simian virus antigens, it was evident occur, especially to international tourists who lack experience that a few monkey forest workers had higher levels of with monkeys, when humans either fail to relinquish food reactivity with simian virus antigens than was evident in or behave in a manner the monkeys deem threatening. In most other monkey forest workers or negative control sera a retrospective study of French tourists seeking medical (Figure 1(a)). Such elevated antibody levels directed against treatment for an animal bite received in Southeast Asia, cross-reactive alphaherpesvirus antigens suggests that these most reportedthattheinjuringanimalwas amonkey[60]. individuals have experienced an infection with a virus anti- Studies have shown that between 6 and 40% of visitors to a genically related to but different from HSV. Further analysis monkey temple will be bitten, and thus it is not surprising that by sensitive competition ELISA [23, 24] conrm fi ed that the zoonotic transmission of a primate retrovirus (simian foamy reactivity of these sera was consistent with that of having virus) has been documented following exposure to macaques been infected with BV (Figure 1(b)). Given the absence of any in Asia [20, 61–63]. history consistent with typical BV infection (i.e., infections with neurological involvement), it is possible that these In addition to the hundreds of monkey temples across persons experienced asymptomatic BV infections. However, Asia, tens of thousands of macaques are free-ranging in urban if asymptomatic BV infections do occur in Asia, then the lack areas such as Singapore, Hong Kong, Delhi, and the famous of apparent asymptomatic BV infections in the US presents a wild monkey parks of Japan. Macaques are also commonly different enigma. found as pets, and a centuries-old tradition of keeping and When assessing the neurovirulence of BV, it is important training performing monkeys continues in China and Japan. Finally, it should be noted that Indonesia, Thailand, Malaysia, to recognize that, within Asia where hundreds of thousands Singapore, Vietnam, Cambodia, Laos, Philippines, China, of macaques come into daily contact with millions of peo- and Japan all have active biomedical research programs ple, there is no conclusive evidence of zoonotic infections, and/or primate breeding research centers which collectively neurological or otherwise. Genetic differences in human employ thousands of workers and involve tens of thousands subjects (Asian versus non-Asian background) would seem of macaques each year. Many of these breeding facilities an unlikely explanation for the lack of fatal BV infections in operate under conditions of extreme animal overcrowding Asia since many non-Asian tourists visiting monkey forests with husbandry and handling protocols that are substan- in Asia and non-Asian military troops serving in Asia have dard (Jones-Engel, pers. observ.). Despite frequent contact experienced bites and scratches from macaques without any between humans and free-ranging, temple, pet, or urban resulting zoonotic BV infections [11, 19, 61, 64]. Similarly, macaques in Asia, fatal cases of BV have only occurred in inaccurate diagnosis of zoonotic BV infections in rural areas the US and Canada following contact with captive macaques. with limited healthcare seems unlikely explanation as tens of This geographic restriction of zoonotic BV infections has long thousands of macaques are free-ranging in large metropolitan been and remains a puzzle. areas in Asia where access to healthcare, diagnostics, and case One immediate question is whether or not BV is even follow-up are readily available (e.g., Singapore, Hong Kong, zoonotically transmitted in Asia. There is no question that and Kyoto). It is even less likely that clinicians in a tourist’s individuals in communities living near macaques or who home country would fail to diagnose BV when presented work in SE Asian monkey forests have a history of extensive with a history of a macaque bite and neurological symptoms. 4 Advances in Virology 1.0 100 0.9 0.8 Normal Macaque Normal human 0.7 (HSV−/BV+) (HSV+/BV−) 0.6 0.5 0.4 0.3 Fatal BV #1 0.2 Fatal BV #2 (HSV+/BV+) (HSV+/BV+) 0.1 0.0 Normal human HSV+ Fatal Monkey temple workers Monkeys BV Temple worker Temple worker HAD43 60 BH9 1 2 3 4 56 7 12 34 567 log competing antigen dilution (a) (b) Figure 1: Evidence of possible asymptomatic BV infections in Asia. (a) Sera from individuals working at monkey forests in SE Asia [19, 20] were tested by ELISA as described [21, 22] against HSV1 (dark blue), HSV2 (light blue), BV (red), HVP2 (orange), squirrel monkey herpesvirus (light green), and spider monkey herpesvirus (dark green) antigens. HSV1 OD values were normalized to 1.0 to assess relative levels of reactivity with cross-reactive antigens. Average levels of cross-reactivity with BV and HVP2 in normal HSV-positive control sera (individuals with no known contact with monkeys) are indicated by the dashed line, and average levels of cross-reactivity with the two S. American monkey viruses are indicated by the dotted line. The four sera from monkey forest workers and serum from a fatal case of zoonotic BV infection have higher levels of cross-reactivity with all simian virus antigens than do control sera. (b) Competition ELISAs were performed as described [23, 24] to determine if sera from monkey forest workers with high levels of cross-reactivity were consistent with having been infected with BV. Soluble antigens (extracts of cells infected with HSV1 (blue), BV (red), or uninfected cells (black)) were used to compete the binding of serum to HSV1 antigen coated onto the ELISA plates. Binding of control HSV1-positive serum was inhibited only by soluble HSV1 antigen, not by BV or control antigens. Binding of BV-positive macaque serum (HSV-negative) to the solid phase HSV1 antigen was equally competed by soluble HSV1 and BV antigens. Binding of sera from two patients that died of zoonotic BV infection (both HSV1-positive) were competed by both HSV1 and BV soluble antigens, although competition by BV antigen was less than by HSV1 antigen. Binding competition forserafromtwomonkeyforestworkers(bothHSV1-positive)wassimilartothatofzoonoticBVpatient sera. Despite being exposed to populations of macaques known to have operated in Asia for decades, some of which contain be BV positive, no cases of zoonotic BV have been reported up to 10,000 macaques, there have been no reported cases among international tourists [65]. of zoonotic BV. eTh macaques housed in these facilities Perhaps a more likely explanation lies in the monkeys, are exported and are a source of animals used in biomed- that is, captive versus free-ranging. Do captive macaques ical research in North America. Other possibilities such as shed BV more frequently as a result of some husbandry recombinant BV in captive monkeys that arose through past practices? When they are shedding do they shed more virus? practices of cohousing of different species during capture and Do free-ranging monkeys preferentially shed virus (or more shipping have also been raised. eTh lack of BV isolates from virus) genitally rather than orally, while captive monkeys shed free-ranging macaques for comparison to BV isolates from more orally? All these are questions that have been examined captive macaques and isolates recovered from zoonotic cases only supercfi ially or not at all. It is particularly intriguing will be necessary to address these and many other aspects of that amongst the dozens of primate breeding facilities that BV neurovirulence. Normalized OD value HSV1+ HSV1+ HSV1+ HSV1+ HSV2+ HSV1+ HSV2+ HSV1+ BV+ Baboon Sq Monkey HAD43 HAD20 HAD48 HAD53 % inhibition of test serum binding Advances in Virology 5 4. Model Systems for Zoonotic BV Infection of a lethal neurological infection in a black-and-white colobus monkey (Colobus guereza) [81]. Given the lower biosafety Rabbits have historically been used as an animal model for rating of HVP2 (BSL2 versus BSL4 for BV), HVP2 is an BV infections. Until recently, all testing of antivirals for anti- attractive model for BV cross-species infections [74, 76]. BV activity was conducted using rabbits [66–70]. Rabbits are however not an ideal model system given their size, the 5. Molecular Aspects of BV relative paucity of immunological reagents, and the difficulty of housing and handling infected animals under stringent From the time of its original isolation in 1932, extensive biohazard conditions. Infant mice were found to be suscepti- antigenic cross-reactivity between BV and HSV has been ble to BV and using this model, the spread of BV in an axonal- noted, indicating that these viruses are closely related [42, 82– transsynaptic manner was demonstrated [71, 72]. However, 85]. Subsequent studies revealed that alphaherpesviruses of this model has a number of inherent drawbacks (immature baboons (HVP2), vervets (SA8), and chimpanzees (ChHV) immune system, size, and dependable numbers/availability) and to a lesser extent the viruses of squirrel monkeys (HVS1) and has not been used further. Infection of young adult andspider monkeys(HVA1)areallclosely related[23,83, 85– mice by intramuscular (i.m.) injection (similar to a bite 90]. Phylogenetic analyses of the alphaherpesviruses based on wound) found substantial variation in the neurovirulence of gene sequences have defined three major clades of primate various strains of BV isolated from rhesus monkeys, but this alphaherpesviruses consisting of the hominid viruses (HSV1, model system was not highly reproducible [73]. However, HSV2, and ChHV), cercopithecine (African and Asian) inoculation of young adult Balb/c mice by skin scarification monkey viruses (BV, HVP2, and SA8), and the platyrrhine (S. of the flank was found to produce disease very similar to American) monkey viruses (HVS1 and HVA1) [91–93]. Based that seen in humans and to be very reproducible [74]. This on the close relatedness of BV and HSV, the relative lack of mouse model has recently been used for testing ecffi acy of research on the simian viruses, and the biohazard concerns in antiviral drugs and molecular studies on BV [75–77]. Lesions working with infectious BV, comparatively little experimental in the brainstem of BV infected mice are characterized by molecular work with BV has been published. us, Th most perivascular cuffing with mononuclear cells, discrete foci of of what is “known” about BV structure, protein functions, neuronal necrosis, gliosis, and discrete areas of destruction and viral replication is actually extrapolationed from what is of white matter within reticular tracts, accompanied by large known for HSV. However, as more work is done with BV and foamy macrophages (gitter cells) similar to those present related simian viruses, significant differences between these in spinal cord lesions. Viral antigen is also present within viruses and HSV become more apparent. neurons and glial cells, and the severity of inflammation BV has the typical virion structure of alphaherpesviruses, is related to the amount of viral antigen present [73]. The the genome being enclosed within an icosahedral capsid inflammatory response to infection has been linked to the that is embedded in an amorphous protein tegument and lethality of HSV encephalitis in mice [78, 79], and an surrounded by a lipid membrane envelope [51, 94]. Like HSV, aggressive inflammatory response in neural tissue may well the lytic replication cycle of BV is rapid with extracellular contribute to the lethality of BV infections in both mice and progeny virus appearing∼6–8 hrs aer ft infection (PI) [95]. humans. And as for HSV, synthesis of BV proteins appears to follow In this mouse model, all BV isolates from rhesus the immediate early/early/late gene expression paradigm. macaques and an isolate from a long-tailed macaque (M. In 1971, an isolate of BV from a rhesus macaque was fascicularis) were found to have similar LD values of adapted to replicate in primary rabbit cells, and this strain approximately 10 PFU [77]. In contrast, isolates from pigtail (E2490) now serves as the “standard” or “laboratory” BV (M. nemestrina) and lion-tailed macaques (M. silenus) were strain [69, 96]. The genome sequence of this strain has not lethal (at 10 PFU) despite producing clinical signs of neu- been determined [97–99]. Recently, genome sequences of rological involvement. This is interesting when one considers a number of additional BV strains from various macaque that most if not all cases of zoonotic BV have been associated species have also been determined [77, 100]. BV genomes with exposure to rhesus or long-tailed macaques rather than range in size from 154,958 to 157,447 bp, the differences being pigtail macaques (lion-tailed macaques are endangered and largely due to variation in the number of iterations of repeated not used in biomedical research). sequence units in specific areas of the genome. eTh BV As mentioned above, the neurovirulence of BV actually genome has a very high G + C content (∼75%) and its genetic relates to its neurovirulence in nonnatural host species. In arrangement is orthologous to that of HSV (Figure 2). Based this regard, it is interesting that no zoonotic infections due to on PCR/sequencing of a small region of the BV genome, the two viruses most closely related to BV, HVP2 of baboons different “genotypes” of BV were identified that correlated (Papio spp.) and SA8 of vervets (Cercopithecus aethiops), with the macaque species the virus was isolated from [24, have been reported (with one probable exception [50]). Both 101, 102]. Comparison of complete genome sequences of baboons and vervets have long been used in biomedical BV isolates from different macaque species confirmed the research and exposure incidents have certainly occurred. It division of BV into host species-based genotypes [77]. While thus appears that when SA8 or HVP2 are transmitted to sequence identity among BV isolates from rhesus macaques humans they both undergo abortive infections. It is thus or between isolates from pigtail macaques is>99%, sequence interesting that most HVP2 isolates have been shown to be identity among different BV genotypes is only ∼89–95%. justasneurovirulentasBVinmice[74,80]andtobethecause Comparing the genome sequences of all BV isolates, most 6 Advances in Virology U U R R R R ‘a’ ’a’ ‘a’ L L S S (a) ∗∗∗ ∗∗∗ ∗∗ ∗ 116 118 120 122 124 126 128 130 132 (b) RL2 (ICP0) RL1 (34.5) RS1 (ICP4) OriS ORF P ORF O LAT RNAs L/ST RNAs Figure 2: Genomic organization of BV. The BV genome is comprised of two unique regions (U and U ) in which open reading frames L S homologous to the UL1–UL56 and US1–US12 genes of HSV are located, respectively (a). eTh U and U regions are each flanked by repeat L S regions (R an R , resp.) with the ‘a’ repeat present at the ends of the genome and between the internal copies of R and R .TheR and R L S L S L S regions are enlarged in (b) to indicate the position of the following features discussed in the text: predicted ORFs (green), HSV ORFs not found in BV (blue), the origin of DNA replication in R (yellow), miRNAs (asterisks), islands of reiterated sequences (magenta), and the region deleted in the E90ΔRL1 mutant (red). coding sequences, miRNAs, and small RNAs are highly structural capsid proteins (which as a functional group are conserved [77, 100, 103, 104]. The most prominent differences the most conserved proteins) and viral enzymes. However, a are located in areas of the long and short repeat regions (R number of BV proteins have regions of dissimilarity relative and R , resp.) of the genome that do not encode proteins, to other simian viruses and even among different genotypes miRNAs, or small RNAs. Within these areas, there are islands of BV. Given the interaction of viral immediate early (IE) of reiterated sequences. While the primary sequence of these proteins with host cell proteins to facilitate expression of the reiterated repeat units and the number of iterations are viral DNA and initiate the lytic replication cycle, it might not conserved among all BV isolates, the positions of these be expected that the IE proteins would be highly conserved. repeat islands are conserved suggesting they likely serve some However, these regulatory IE proteins are actually some of the unknown function. least conserved, both among BV genotypes and between BV The genome of BV (as well as HVP2 and SA8) is very and other primate viruses. By virtue of their expression on the similar to that of HSV2 and ChHV in its genetic organization, surfaceofvirions andinfectedcells,glycoproteins andother with homologs of almost every HSV gene being present in the membrane associated proteins are another group of proteins same order and orientation in BV [77, 92, 99, 105, 106]. er Th e that likely interact with elements of host cells. While some are some minor differences like the grouping of some genes are strongly conserved (>90%AAsequenceidentity), others into different cotranscriptional units [107]. However, there are very poorly conserved (<62% AA identity). Consistent is one major difference, that being the lack of a detectable with this, a number of glycoproteins have some degree of homolog of the RL1 (𝛾34.5) and ORF P genes in the simian virus-specific antigenicity. The gB (UL27) and gD (US6) viruses [92, 99, 105, 106]. This was somewhat unexpected glycoproteins are major immunogens of BV, and while both as both of these genes have been shown to be involved arestructurallyconserved andhavemanycross-reactiveepi- in neurovirulence of HSV (see below). It should be noted topes, each also has some degree of antigenic BV-specificity however that none of the alphaherpesviruses of nonprimate [70,87,108,109,116,117].BoththegG(US4)andgC (UL44) animals have homologs of the RL1 or ORF P genes either. glycoproteins are much less conserved and are largely BV- Based on DNA sequence data, variation in predicted specific antigens with respect to HSV, but still exhibit some amino acid (AA) sequence identity of homologous BV and antigenic cross-reactivity with the homologous glycoproteins HSV2 proteins averages 62.5% [99]. In contrast, average of HVP2 and SA8 [25, 109, 110, 116, 118–120]. Regardless of AA sequence identity values are approximately 95% among the degree of conservation/divergence of BV proteins from BV strains, 87% between BV and HVP2, and 83% between those of other related viruses, with one exception there are BV andSA8[100,105,106]. ThislevelofAAsequence no studies where the involvement of specific BV proteins homology is consistent both with previous studies that in neurovirulence has been examined. The one exception is detected antigenic cross-reactivity of almost all BV proteins the UL41 gene which encodes the virion host shutoff (VHS) with homologous proteins of HSV [83, 87, 108–111] and with protein. Deletion of this ORF does not cause a signicfi ant the extensive antigenic cross-reactivity observed between BV reduction in the LD of BV in mice [75]. While BV encodes homologs of all the various HSV and HSV in ELISA, western blot, and neutralization assays [84–86, 112–115]. proteins mentioned above, little is known about these BV The highly conserved nature of most HSV, ChHV, and proteins regarding functional equivalency to their HSV coun- simian virus proteins argues for the homologous proteins of terparts. BV glycoproteins gC (UL44) and gD (US6) as well each virus having similar functions. Certainly this is true for as VHS (UL41) have been shown to have similar structural Advances in Virology 7 and functional properties to their HSV homologs [75, 117, not lethal in mice). It remains to be seen if UL39 underlies 120–122]. While AA homology suggests that BV proteins neurovirulence of BV in mice as it does in HVP2. function much as their HSV homologs do, the functional The HSV R1 protein is involved in evasion of cell death equivalency of all other BV proteins has not been directly by preventing necroptosis in human but not mouse cells examined. As one example, the BV ICP0 (RL2) homolog [129–131]. In mouse cells, the HSV R1 protein interacts with has the characteristic RING n fi ger domain and many other receptor interacting kinase 1 (RIP1) and RIP3 via their RIP structural motifs of the HSV ICP0 (phosphorylation sites, homotypic interaction motifs (RHIMs) which is also present USP7/ND10 localization region, nuclear localization signal, in the N-terminal region of HSV R1, and this interaction and multiple SIM-like sequences [123]). While this certainly ultimately leads to formation of necrosomes and death of indicates that the BV ICP0 protein is structurally very similar the infected cell. In human cells, R1 disrupts the interaction to the HSV ICP0 protein, the actual functional equivalency between RIP1 and RIP3, also in a RHIM-dependent manner, of BV ICP0 has yet to be demonstrated. Furthermore, while thereby preventing necroptosis. Both the BV and HVP2 R1 these various structural motifs are evident, even minor proteins contain this RHIM motif, and the sequence in this differences in their primary AA sequence could have an effect smallareaishighlyconserved.Thereishowever onesubtype- on their differential function in epithelial versus neuronal specific AA substitution in the RHIM of HVP2ap/nv R1, but cells or macaque versus human-macaque cells. the AA residue present in nonneurovirulent HVP2ap isolates is thesameasthatpresentinallBVisolatesthatarelethalin Although not examined in BV, the UL39 gene is inter- mice,suggestingthatthisAAmaynotberesponsibleforthe esting with regard to host-specific neurovirulence. Despite HVP2 neurovirulence phenotype. the lack of any clinical differences in its natural baboon host, phylogenetic analyses and testing in mice place HVP2 6. Does BV Have a Functional Homolog of isolates into two distinct subtypes [26, 80, 124]. One subtype the HSV RL1 (𝛾34.5) Neurovirulence Gene? (HVP2ap) produces no clinical signs of infection in mice following infection with as much as 10 PFU but does induce InHSVboththeRL1(𝛾34.5) gene encoding the ICP34.5 (RL1) an adaptive immune response. In contrast, isolates of the sec- proteinandtheORF Pgene(ontheoppositestrandand ond subtype (HVP2nv) are extremely neurovirulent in mice, overlapping the RL1 gene) have been shown to be primary having an LD of ∼10 PFU (like BV). This dichotomous determinants of neurovirulence in mice [132–137]. Given the mouse-specific neurovirulence phenotype of HVP2 isolates neurovirulent reputation of BV, the finding that BV lacks allowedmappingoftheneurovirulencelocus.Recombi- homologs of both the RL1 and ORF P genes was not expected. nant HVP2ap/nv viruses were constructed and tested for The HSV RL1 coding sequence starts approximately 200 bp neurovirulence in mice. Correlation of the neurovirulence from the internal copy of the ‘a’ repeat (Figure 2). However, phenotype with genome sequence analyses (defining which no ATG initiation codon is apparent within 500 bp of the ‘a’ parts of the genome were derived from HVP2ap versus repeat in any BV strain (or in HVP2 or SA8). Similarly, no HVP2nv) identified a limited region of 3-4 genes that was potential termination codon is present in any of the simian associated with the neurovirulence phenotype. Based on viruses near the initiation point of the L/ST RNAs where this, the UL39 gene was the most likely candidate for the the HSV RL1 termination codon is located. Furthermore, no predicted AA sequence homology exists in the “RL1 region” “neurovirulence gene,” and this was ultimately confirmed by in any of the simian viruses. u Th s, multiple investigators have construction and testing of UL39 ORF-specicfi recombinant been unable to identify a simian virus homolog of the RL1 viruses[125].Thus,replacingtheUL39apcodingsequence or ORF P genes [77, 99, 100, 105, 106]. Despite the lack of with the UL39nv coding sequence makes an HVP2ap virus a discernable simian homolog of the HSV RL1 gene (or an neurovirulent, and vice versa. overlapping ORF P gene on the opposite strand), the RL1 The UL39 gene encodes the large subunit of the ribonu- region between the RL2 start codon and the ‘a’ repeat of cleotide reductase protein (R1). UL39 has been associated the simian virus genomes (1844–2146 bp) is about the same with neurovirulence in HSV (the ability to replicate in size as in HSV and ChHV (2048–2154 bp). This suggests that nondividing nerve cells) and is one of several genes deleted despite the lack of discernable homologs of the RL1 and ORF from prototype HSV gene delivery vectors [126]. While the C- P genes, this region of the simian virus genomes serves some terminal∼75% of the R1 protein is highly conserved and has function. While there are no apparent ORFs in this region of homology to mammalian ribonucleotide reductase proteins, BV,there aretwoislandsofreiteratedsequences,and RNA theN-terminalregionsoftheHSV,HVP2,andBVR1proteins structural analysis of this region (which includes the 5 part are unrelated to other known proteins and (in HSV) are not of the L/ST RNAs) indicates a plethora of potential stem-loop essential for ribonucleotide reductase enzymatic activity [127, secondary structures. The sequence in this region is highly 128].ItisthisN-terminalregionthatisdistinctinthetwo conserved among 15 strains of BV from rhesus macaques HVP2 subtypes, implying that the N-terminal region of the but not between BV isolates from different macaque species. UL39 protein in some way determines the neurovirulence of Whether or not this region encodes functions similar to those HVP2 in mice. Interestingly, this region of BV UL39 exhibits of HSV is not known. similarly extensive sequence variation between BV isolates Comparing the RL1 region sequences of simian virus from rhesus/long-tailed macaques (that are neurovirulent genomes, there are some conserved features. As in HSV2 and in mice) and pigtail/lion-tailed macaque isolates (that are ChHV, the three simian viruses all have three miRNAs, a 8 Advances in Virology BV isolates Mock HSV1 HVP2 E2490 E90-136 12930 20620 24105 32425 Hrs PI: 1 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 1 4 Figure 3: Lack of eIF2𝛼 dephosphorylation by BV. Cells were harvested at 1 or 4 hrs PI and western blots were performed with antibody directed against phosphorylated eIF2𝛼 (Cell Signaling Technologies; Danvers, MA) as described [25]. No change in the level of phosphorylated eIF2𝛼 was evident in mock infected cells and the amount of phosphorylated eIF2𝛼 decreased from 1 to 4 hrs PI in HSV1 infected cells. In contrast, phosphorylated eIF2𝛼 levels increased in BV infected cells. potential TATA sequence, and both ICP4 and SP1 binding following infection (Figure 3). Quite the opposite, accumu- site motifs that are likely control elements for transcription of lation of phosphorylated eIF-2𝛼 is readily evident in BV L/ST RNAs [138]. There is also a potential ORF P start codon infected cells. How BV continues to replicate while eIF-2𝛼 is located approximately 760–815 bp 5 of these putative L/ST phosphorylated is not known. transcriptional control elements in all three simian viruses Using the deletion/replacement approach described for (in HSV the ORF P start codon is 3 of the L/ST control other genes [75, 125], a BV mutant (E90ΔRL1) lacking 1162 bp elements). The translated sequence from this start codon in in the RL1 region but retaining 5 transcriptional control BV is conserved only for the initial four codons (M-A-A- elements of the RL2 (ICP0) gene and 2 of 3 miRNAs located R/E), aer ft which no discernable sequence homology exists. adjacent to the ‘a’ repeat was constructed. This mutant Whether this possibly represents an actual start codon to a growsaswellasthe parental wild-typevirus inVero cells, spliced gene or is simply the result of sequence similarity due indicating that this region of the genome is not essential for to the extremely high G + C content of this region (producing BV replication in vitro. When proteins synthesized at various a strong bias towards high-GC codons) is unknown. It times PI were examined (1-2, 4–6, 10–12, and 4–24 hrs PI), may also be that this potentially conserved AA sequence no differences were detectable between the parental wild- is completely irrelevant, conserved DNA sequence instead type virus and the E90ΔRL1 mutant. In primary mouse skin representing part of the conserved transcriptional start site fibroblasts infected at a low multiplicity of infection (MOI; of the L/ST RNAs. 0.3 PFU/cell), wild-type BV forms small plaques by 24 hrs PI HSV mutants lacking the RL1 or ORF P genes are and subsequently spreads to adjacent cells involving the entire attenuated in a number of mouse model systems, and they fail cell monolayer by 48 hrs PI (Figure 4). In contrast, while to spread within the nervous system even when inoculated the E90ΔRL1 mutant also forms small plaques by 24 hrs PI, directly into the brain [132–134, 137]. The ICP34.5 protein these fail to spread with time. Quantitation of infectious playsacrucialroleinallowingHSVtoevadethe host virus produced aeft r low MOI infection reflected this, in innate immune response by blocking MHC II expression that while the E90ΔRL1 mutant does replicate, the amount on the surface of infected cells. When infected, cells ini- of infectious progeny produced at 24 hrs PI is significantly tiateanantiviralinterferonresponsethatprimarily aeff cts less than that produced by wild-type BV. Since Vero cells neighboring uninfected cells making them more resistant to do not produce IFN-𝛽 while primary mouse cells do, this infection, and ICP34.5 deletion mutants are very sensitive suggests that deletion of the RL1 region from the BV genome to this host antiviral IFN-𝛼/𝛽 response [139–141]. Another renders the virus susceptible to the host IFN-𝛽 response. eTh host cell response to infection is activation of double- E90ΔRL1 mutant does however effectively suppress the host stranded RNA-dependent protein kinase (PKR). PKR acts to IFN-𝛽 response when cells are infected with a high MOI, phosphorylate translation initiation factor eIF-2𝛼 resulting in suggesting that low MOI infection with the E90ΔRL1 mutant cessation of protein synthesis in the cell. eTh HSV ICP34.5 allows adjacent uninfected cells to initiate an effective IFN- 𝛽 protein dephosphorylates eIF-2𝛼, thus counteracting eIF- response that the mutant is unable to overcome, preventing 2𝛼 phosphorylation-induced autophagy [142–146]. The C- further spread of the virus. In this respect, the BV RL1 region terminal region of ICP34.5 has homology with GADD34 deletion mutant appears similar to ICP34.5 mutants of HSV. protein which facilitates its interaction with the MyD116 and The E90 ΔRL1 mutant was also tested in mice using the PCNA cell proteins to form a DNA-binding complex [139, skin scarification model to assess what effect this region 146, 147]. ICP34.5 thus appears to be of central importance has on neurovirulence. As mentioned above, HSV mutants to the HSV replicative cycle in many ways. Given the impor- lacking the RL1 gene are not neurovirulent in mice and tance of ICP34.5 functions in HSV, the close relatedness of fail to spread within the nervous system. In contrast, the BV and HSV, and the similar size of the RL1 region of the neurovirulence of the E90ΔRL1 mutant was actually slightly genomes, it is reasonable to hypothesize that this region of increasedrelativetothatoftheparental wild-typevirus,the 3.7 4.4 the genome may serve some similar function(s) in all these mutant having an LD of 10 PFU compared to 10 PFU viruses. However, unlike HSV none of the simian viruses for the parental virus. Even so, the time to death/euthanasia display the ICP34.5 function of eIF-2𝛼 dephosphorylation of infected mice was the same for both viruses (5.5–6 days Advances in Virology 9 24 hrs PI 48 hrs PI E90-136 E90Δ RL1 Figure 4: Deletion of the RL1 region affects BV spread in primary mouse ce lls. Primary murine skin b fi roblast cells were prepared, cultured, and infected as described [26]. At low MOI (0.3 PFU/cell) wild-type BV (E90-136) forms plaques by 24 hr PI and rapidly spreads over the next 24 hrs, while the E90ΔRL1 deletion mutant fails to spread after 24 hrs PI. PI). u Th s, the RL1 region of BV does not appear to encode all allow direct infection of sensory neurons) [148–151]. Second, thesamefunctions ascribedtothe𝛾34.5 protein of HSV and once within a sensory neuron, the linked processes of viral is not a major determinant of BV neurovirulence. replication, establishment of latency, and reactivation from latency could aeff ct the spread of BV within the nervous system. 7. What Else Could Underlie the Extreme Neurovirulence of BV in Replication at the Site of Infection. The occurrence of herpetic Non-Macaque Hosts? lesions at injury sites in zoonotic BV patients suggests that BV can replicate effectively in human epithelial tissue. However, One possibility that has been raised to explain the restriction the rarity of zoonotic BV infections relative to the number of of zoonotic BV cases to North America is that some BV annual exposure incidents that occur and the apparent lack isolates circulating in these captive macaques are potentially or rarity of asymptomatic zoonotic infections could indicate recombinant viruses, the recombinant viruses having arisen that zoonotic transmission of BV does not always lead to an due to past practices of cocaging monkeys of different species active or clinically apparent infection in many or even most during importation. Sequencing of multiple BV isolates from cases. This could be due to any number of things including (1) different US rhesus breeding colonies failed to detect any such monkeys not shedding virus at the time of contact; (2) too low recombinants [77]. However, none of the isolates examined levels of virus transmitted to overcome preexisting (cross- were from zoonotic BV cases. Comparative genome sequenc- reactive) immunity to HSV; or (3) innate host resistance ing of BV isolates from zoonotic cases and from monkeys resulting in inefficient or abortive replication of BV in human could determine if there are specific characteristics (including epithelial cells relative to its ability to replicate in macaque recombinants) that are associated with zoonotic isolates but cells. While it has been shown that HSV replication in rhesus not present in all monkey isolates. In addition, sequencing of cells can be very inefficient or abortive [152–154], such has not BV isolated from free-ranging (noncaptive) monkeys would been shown for BV replication in human cells. A failure of servetoidentifythepresenceofrecombinantvirusesinNorth BV to replicate well in humans at the original site of infection American captive macaques. resulting in insufficient levels of virus to invade sensory In assessing the host-specific nature of BV neuroviru- neurons could result in the majority of exposure incidents lence, differences that occur in how the virus behaves in not leading to active zoonotic BV infections, such cases only the natural versus nonnatural host obviously need to be resulting when high enough levels of infectious virus are examined. There are really two critical points where differ- transmitted to allow infection of sensory neurons without ences in host-virus interactions in humans and macaques need for further amplification of virus by local replication. would most probably aeff ct neurovirulence/clinical disease. Recent studies have begun to investigate the comparative The first is the ability of BV to invade the nervous system. replication of BV in macaque versus human cells. It has been In the normal course of pathogenesis, viral replication in shown that while the HSV gD glycoprotein binds host cell epithelial tissue at the site of inoculation is needed to produce sufficient levels of infectious progeny virus to allow invasion proteins HVEM, nectin 1 and nectin 2 to facilitate viral entry, the BV gD glycoprotein only binds nectin 1 and nectin 2 of sensory neurons innervating the site (this is not necessary if sufficiently high levels of infectious virus are transmitted to in both human and macaque cells [121, 122, 155]. While a 10 Advances in Virology single amino acid mutation was identified in the external repression of the BV genome in human neurons could well domain of gD that aeff cted the stability of binding to nectin result in a very different outcome of infection compared to that seen in macaques. 1, comparison of gD sequences from 19 clinical BV strains isolated from humans and macaques found that this mutation As mentioned previously, there is evidence supporting the ability of BV to establish latent infections in humans and to did not correlate with zoonosis [117], indicating that differing reactivate at later times just as occurs in macaques. Even so, stability of gD binding to nectin 1 is not related to the ability of BV to infect human versus macaque cells. Consistent with slight alterations in the most basic molecular aspects of these processes could have a radical effect on the ultimate outcome this, the gD glycoprotein has been shown to be altogether of BV infections in humans. It may be that in human neurons dispensable for BV entry into both macaque and human cells BV usually overcomes the innate preemptive response of [155]. the neuron to effectively repress viral IE gene expression The HSV IE protein ICP47 (US12) mediates downregu- and establish latency. This would result in lytic replication lation of MHC expression on the surface of infected cells, of BV in human neurons with production of progeny virus thus likely evading activation of host antiviral T cells and and subsequent spread of the virus to other neurons and/or altering susceptibility of infected cells to killing by natural accessory cells. Given the apparently central role played by killer (NK) cells [156]. eTh BV ICP47 protein lacks the TAP- the multifunctional ICP0 protein in the establishment of binding domain of the HSV ICP47 and thus BV fails to latency [123, 161], variant interaction of the BV ICP0 protein downregulate MHC expression in both human and macaque with macaque versus human cell factors could well be a cells, suggesting that the differences in BV and HSV evasion critical factor. of activation of antiviral T cells and susceptibility to NK When reactivated from latency, progeny virions (or virion cells are not responsible for any differential pathogenicity components) are transported anterograde down the axon of BV in humans versus macaques [157]. Similarly, PI3K- where the virus exits the neuron and undergoes lytic repli- dependent Akt phosphorylation (which promotes survival cation in epithelial tissue [148, 162]. While details of how of the infected cell and inhibits apoptosis) is not markedly reactivation from latency occurs are not known, reactivation different in macaque and human b fi roblasts [158]. us, Th there undoubtedly once again involves altered interactions between is no evidence to date to suggest that BV replicates much the latent viral genome and host cell factors aeff cting IE gene differently in human versus macaque epithelial cells. transcription. Since HSV latency associated transcripts (LAT) and both small RNAs and miRNAs appear to be primarily Replication, Latency, and Reactivation in Neurons. Virtually involved in maintaining latency [138, 160], differential expres- nothing is known regarding details of the establishment of sion and/or function of homologous BV RNAs in macaque BV latency or reactivation from latency. However, based on versus human neurons could alter the stability of the latent what is known about HSV, some predictions can be made state in the two species. While some miRNAs and small RNAs aboutwhatmightoccurdieff rentlyintheseaspectsofBV have been identified and mapped in BV [103, 104], nothing is in its natural versus nonnatural host. When HSV infects known about BV LATs or functions of these RNAs. a neuron, the viral envelope fuses with the cell plasma Since reactivation from latency must involve replication membrane, releasing the nucleocapsid and tegument proteins of the virus in the neuron, it has been hypothesized that into the cytoplasm. eTh nucleocapsid (or at least the viral replication and production of progeny virus in neurons is DNA) is transported to the nucleus where the viral DNA much less efficient than in epithelial cells, thereby sparing is immediately coated with histones and cellular repressor widespread destruction of host neurons [163]. This could proteins to prevent viral IE gene expression and entry into well be the case in macaques, but not when BV reactivates the lytic replication cycle, resulting in latency [159, 160]. in human neurons. Instead, BV may replicate much more To counteract this, the viral tegument protein VP16 (UL48) efficiently in human neurons compared to macaque neurons, recruits several host cell proteins to form complexes at IE gene resulting in production of more virus within the nervous promotors that facilitate expression of the viral IE genes and system andmoreecffi ient spread of BV within thehuman progression into the lytic replication cycle [159]. At the same nervous system as seen in fatal zoonotic infections. time, the ICP0 (RL2) IE protein, which is also present in the A similar possibility is that while BV may become latent tegument, degrades host cell proteins involved in repressing in humans, it is reactivated much more readily in humans viral gene expression via its E3 ubiquitin ligase activity. ICP0 than in macaques (days as opposed to months or years). This also competitively binds to certain components of repressor wouldbeconsistentwiththe variabletime (daystoseveral complexes, thus destabilizing the repressor complexes and weeks) between exposure incidents and the first appearance tilting the balance against entry into the lytic replication cycle of clinical symptoms in zoonotic BV patients [5, 46, 51]. In the and favoring latency [123, 161]. This fine balance between natural host, it is likely that only small amounts of infectious lytic replication in neurons and establishment of latency virus are produced in neurons following reactivation from represents an exquisite degree of coadaptation between HSV latency and progeny virions are transported anterograde in anditshumanhost,allowing both tocoexist.Itislikelythat the axon down to the original epithelial site of infection BV follows this same paradigm in macaques, becoming latent where further replication occurs until cleared by an adaptive in sensory neurons with the host adaptive immune response immune response. If reactivation of BV from latency is clearing the initial infection in epithelial tissue. Anything much more efficient in human neurons, it is conceivable that that alters this fine balance between lytic replication and BV could eventually overload the host/virus balance with Advances in Virology 11 successive waves of newly replicated virus infecting many this region of the simian virus genome remains nearly the more neurons than occurs in the natural macaque host. same size as in HSV. Although both the RL1 and ORF P genes Another possibility is that in humans BV is more readily are important determinants of HSV neurovirulence in mice, transported down dendrites than in macaques, resulting deletion of this region of the BV genome has little eeff ct on its in more efficient spread of the virus within the human neurovirulence in mice. nervous system. Interestingly, in pseudorabies virus (PRV; BV has attained its reputation as having extreme neu- a porcine alphaherpesvirus), there does appear to be some rovirulence due to the high mortality associated with the virus-specificity in attachment of virions to dynein motor approximately 60 zoonotic cases that have occurred since proteins (for axonal transport) versus kinesin motor proteins its identification 85 years ago. However, for comparison (for axonal and/or dendritic transport) [164]. Binding to HSV causes ∼500 cases of encephalitis each year in the kinesin motors involves the gE (US8), gI (US7), and US9 US, and without treatment is∼70% fatal with only∼5% of proteins of PRV, while tegument proteins UL36, UL37, and patients fully recovering [18], characteristics that are very US3 impart affinity for dynein motors. u Th s, even slightly similar to that of zoonotic BV. The neurovirulence of BV is altered specificity of any of the homologous BV proteins for only apparent when it infects non-macaques. While there macaque versus human dynein or kinesin motor proteins are some differences between HSV and BV, to date no could affect the neurovirulence of BV in humans by altering differences in the replication of BV in vitro in human versus the spread of infection from that which occurs in the natural macaque cells have been identified that might account for the macaque host. The failure to establish latency in human divergent neurovirulence of BV in these two species. Given neurons, altered stability of latency, and altered spread of the delicate balance that exists in neurons between repression the virus within the nervous system are all consistent with of gene expression to establish latency and lytic replication, the very serious CNS infection versus no infection picture of even slight differences in any of the multitude of host-virus zoonotic BV infection that seems to occur in humans. interactions aeff cting this balance could ultimately alter the pathogenesis of BV in a nonnatural host species, resulting in very different outcomes of infection in macaques versus 8. Conclusions humans. Considerably more research into molecular aspects BV is ubiquitous in populations of captive and free-ranging of host-virus interactions in macaque versus human cells, macaques and despite many exposure incidents every year; both epithelial and neural, needs to be pursued to better understand the extreme neurovirulence exhibited by BV in zoonotic infections are extremely rare and have only been documented in North America. Notwithstanding, BV is humans. notorious for its extreme neurovirulence in the handful of humans who have been infected. Biological aspects of BV Ethical Approval infection in its natural macaque host are very similar to that of HSV in humans, including primary replication in Serum samples from humans and monkeys were all collected epithelial tissue, invasion of sensory neurons, establishment under approved Institutional Review Board (human) or of latency in sensory ganglia, and periodic reactivation from Institutional Animal Care and Use Committee (monkey) latencyinresponsetostressallowingtransmissionofthe protocols. virus to a new host. Phylogenetic analysis of the primate alphaherpesviruses suggests that these viruses have likely Conflicts of Interest coevolved with their hosts, not surprising given the exquisite details that must be involved in virus-host interactions to eTh authors declare that there are no conflicts of interest maintain the virus within the nervous system for the lifespan regarding the publication of this article. of its host without serious adverse consequences while still allowing transmission and perpetuation of the virus within the host species. Given that nonhuman primates are our Acknowledgments closest phylogenetic relatives, it is not surprising that BV The authors wish to thank Drs. C. Jones, K. Ohsawa, and should be very much like HSV with regard to the virus-host J. d’Offay for helpful discussions and critical review of this interactions and mechanisms involved in maintaining the manuscript and DA Leib for eIF2 western blots. This work virus-host relationship in a balanced state. eTh orthologous nature of the BV and HSV genomes and similarity of encoded was supported by PHS Grant R24 OD022013. proteins support this. Based on comparative sequence analy- ses, it also appears that BV encodes LATs, miRNAs, and small References RNAs that would be involved in the intricate regulation of viral latency in neurons as in HSV. [1] D. Elmore and R. Eberle, “Monkey B virus (Cercopithecine Duetothehazardousandrestrictivenatureofperforming herpesvirus 1),” Comparative Medicine,vol.58, no.1,pp.11–21, research with infectious BV, very little experimental or 2008. molecular research has been done on this intriguing virus. To [2] J.L.Huff andP.A.Barry,“B-virus(Cercopithecine herpesvirus date the only genetic characteristic that differs dramatically 1) infection in humans and macaques: Potential for zoonotic betweenBVand HSVisthe lack of homologs of theRL1 disease,” Emerging Infectious Diseases,vol.9,no.2,pp.246–250, (𝛾34.5)andORFPgenesinBV.Despitelacking thesegenes, 2003. 12 Advances in Virology [3] S. A. Keeble, G. J. Christofinis, and W. Wood, “Natural Virus-B [20] L. Jones-Engel, G. A. Engel, M. A. Schillaci et al., “Primate- infection in rhesus monkeys,” The Journal of Pathology ,vol.76, to-human retroviral transmission in Asia,” Emerging Infectious no. 1, pp. 189–199, 1958. Diseases, vol. 11, no. 7, pp. 1028–1035, 2005. [4] A. E. Palmer, “Herpesvirus simiae: historical perspective,” [21] R. Eberle and J. K. Hilliard, “Serological evidence for variation in the incidence of herpesvirus infections in different species of Journal of Medical Primatology,pp. 16–99, 1987. apes,” Journal of Clinical Microbiology,vol.27,no.6,pp. 1357– [5] B. J. Weigler, “Biology of B Virus in Macaque and Human Hosts: 1366, 1989. A Review,” Clinical Infectious Diseases,vol.14,no.2,pp.555–567, 1992. [22] R. Eberle, “Evidence for an alpha-herpesvirus indigenous to mountain gorillas.,” Journal of Medical Primatology,vol.21, no. [6] H.T.ZwartouwandE.A. Boulter,“ExcretionofBvirus 5,pp.246–251,1992. in monkeys and evidence of genital infection,” Laboratory Animals,vol.18, no.1,pp. 65–70, 1984. [23] E. Luebcke, E. Dubovi,D.Black,K.Ohsawa, andR.Eberle, “Iso- lation and characterization of a chimpanzee alphaherpesvirus,” [7] H.T.Zwartouw,J.A.Macarthur,E.A.Boulter,J.H.Seamer,J.H. Journal of General Virology,vol.87,no.1,pp.11–19, 2006. Marston, and A. S. Chamove, “Transmission of B virus infection between monkeys especially in relation to breeding colonies,” [24] S. A. Thompson, J. K. Hilliard, D. Kittel et al., “Retrospective Laboratory Animals,vol.18, no.2,pp.125–130,1984. analysis of an outbreak of B virus infection in a colony of DeBrazza’s monkeys (Cercopithecus neglectus),” Comparative [8] M.R.Andrade,J.Yee,P.Barry etal.,“Prevalenceofantibodies Medicine,vol.50, no.6,pp.649–657, 2000. to selected viruses in a long-term closed breeding colony of rhesus macaques (Macaca mulatta) in Brazil,” American Journal [25] E. L. Blewett, D. Black, and R. Eberle, “Characterization of of Primatology,vol.59,no.3,pp. 123–128,2003. virus-specific and cross-reactive monoclonal antibodies to Her- pesvirus simiae (B virus),” Journal of General Virology,vol.77, [9] R.F.DiGiacomo andK.V.Shah,“Virtualabsenceofinfection no. 11, pp. 2787–2793, 1996. with Herpesvirus simiae in colony-reared rhesus monkeys (Macaca mulatta), with a literature review on antibody preva- [26] K.M.Rogers,D.H.Black,andR. Eberle,“Primarymouse lence in natural and laboratory rhesus populations.,” Laboratory dermal bro fi blast cell cultures as an in vitro model system for Animals,vol.22, no.1,pp. 61–67, 1972. the differential pathogenicity of cross-species herpesvirus papio 2 infections,” Archives of Virology,vol.152,no. 3,pp.543–552, [10] K.Jensen,F.Alvarado-Ramy,J.Gonzalez-M ´ art´ınez, E. Kraisel- burd, and J. Rullan, ´ “B-Virus and Free-Ranging Macaques, Puerto Rico,” Emerging Infectious Diseases,vol.10, no.3,pp. [27] S. A. Keeble, “B virus infection in monkeys,” Annals of the New 494–496, 2004. York Academy of Sciences,vol.85, no.3,pp. 960–969, 1960. [11] L. Jones-Engel, G. A. Engel, J. Heidrich et al., “Temple monkeys [28] E. A. Boulter, “eTh isolation of Monkey B virus (Herpesvirus and health implications of commensalism, Kathmandu, Nepal,” simiae) from the trigeminal ganglia of a healthy seropositive Emerging Infectious Diseases,vol.12, no.6,pp.900–906, 2006. rhesus monkey,” Journal of Biological Standardization,vol.3,no. 3,pp.279-280,1975. [12] M. J. Kessler and J. K. Hilliard, “Seroprevalence of B Virus (Herpesvirus simiae) antibodies in a naturally formed group of [29] J. L. Melnick and D. D. Banker, “Isolation of B virus (herpes rhesus macaques,” Journal of Medical Primatology,vol.19,no.2, group) from the central nervous system of a rhesus monkey,” pp. 155–160, 1990. eTh Journal of Experimental Medicine ,vol.100,no. 2, pp.181– 194, 1954. [13] F.Lee,Y.-J.Lin,M.-C.Deng,T.-Y.Lee,andC.-C.Huang,“Preva- lence of antibody reaction with cercopithecine herpesvirus 1 [30] A. D. Vizoso, “Recovery of herpes simiae (B virus) from both antigen in Macaca cyclopis, Macaca fascicularis, and Papio primary and latent infections in rhesus monkeys,” Journal of anubis in Taiwan,” Journal of Medical Primatology,vol.36, no. Experimental Pathology, vol. 56, no. 6, pp. 485–488, 1975. 6, pp. 343–347, 2007. [31] D.C. Anderson,R.B.Swenson,J.L.Orkin, S.S.Kalter,and H. [14] M.-H. Lee, M. K. Rostal, T. Hughes et al., “Macacine herpesvirus M. McClure, “Primary Herpesvirus simiae (B-virus) infection 1 in long-tailed macaques, Malaysia, 2009-2011,” Emerging in infant macaques,” Laboratory Animals,vol.44,no.5,pp. 526– Infectious Diseases, vol. 21, no. 7, pp. 1107–1113, 2015. 530, 1994. [15] Q. Lin, G.-L. Yuan, L. Ai, J. Li, and H.-L. Li, “Seroprevalence of [32] C.S.Carlson,M. G. O’Sullivan,M.J.Jayoetal.,“FatalDis- BV (Macacine herpesvirus 1) in bred cynomolgus monkeys in seminated Cercopithecine Herpesvirus 1 (Herpes B) Infection Cambodia,” Journal of Veterinary Medical Science,vol.74, no.3, in Cynomolgus Monkeys (Macaca fascicularis),” Veterinary pp.355-356,2012. Pathology, vol. 34, no. 5, pp. 405–414, 1997. [16] R. P. Orcutt,G.J.Pucak,H.L.Foster, J. T. Kilcourse,andT. [33] M. D. Daniel, F. G. Garcia, L. V. Melendez, R. D. Hunt, J. Ferrell, “Multiple testing for the detection of B virus antibody O’Connor, and D. Silva, “Multiple Herpesvirus simiae isolation in specially handled rhesus monkeys aeft r capture from virgin from a rhesus monkey which died of cerebral infarction,” trapping grounds,” Laboratory Animals,vol.26,no.1,pp. 70–74, Laboratory Animals,vol.25,no.3,pp.303–308,1975. [34] M. A. Simon, M. D. Daniel, D. Lee-Parritz, N. W. King, and [17] B. J. Weigler, J. A. Roberts, D. W. Hird, N. W. Lerche, and J. D. J. Ringler, “Disseminated B virus infection in a cynomolgus K. Hilliard, “A cross sectional survey for B virus antibody in a monkey,” Laboratory Animals,vol.43, no.6,pp.545–550, 1993. colony of group housed rhesus macaques,” Laboratory Animals, [35] J.L.Hu,R ff .Eberle,J.Capitanio,S.S.Zhou, andP.A.Barry, vol. 40, no. 3, pp. 257–261, 1990. “Differential detection of B virus and rhesus cytomegalovirus [18] R. J. Whitley and J. W. Gnann, “Viral encephalitis: familiar in rhesus macaques,” JournalofGeneral Virology,vol.84, no.1, infections and emerging pathogens,” The Lancet , vol. 359, no. pp.83–92,2003. 9305, pp. 507–513, 2002. [36] B. J. Weigler, D. W. Hird, J. K. Hilliard et al., “Epidemiology of [19] G. A. Engel, L. Jones-Engel, M. A. Schillaci et al., “Human expo- Cercopithecine Herpesvirus 1 (B Virus) Infection and Shedding sure to herpesvirus B-seropositive Macaques, Bali, Indonesia,” in a Large Breeding Cohort of Rhesus Macaques,” The Journal of Emerging Infectious Diseases,vol.8,no.8, pp.789–795,2002. Infectious Diseases, vol. 167, no. 2, pp. 257–263, 1993. Advances in Virology 13 [37] E.C. Weir,P.N.Bhatt,R.O.Jacoby,J.K.Hilliard,and [54] J. Fierer, P. Bazeley, and A. I. Braude, “Herpes B virus S. Morgenstern, “Infrequent shedding and transmission of encephalomyelitis presenting as ophthalmic zoster: A possible Herpesvirus simiae from seropositive macaques,” Laboratory latent infection reactivated,” Annals of Internal Medicine,vol.79, Animals,vol.43,no.6,pp. 541–544,1993. no. 2, pp. 225–228, 1973. [38] G.J.Chellman,V.S.Lukas,E.M.Eugui,K.P.Altera, S.J. [55] C. Calvo, S. Friedlander, J. K. Hilliard et al., “Case Report: Reac- Almquist, and J. K. Hilliard, “Activation of B virus (Herpesvirus tivation of latent B virus (Macacine herpesvirus 1) presenting simiae) in chronically immunosuppressed cynomolgus mon- as bilateral uveitis, retinal vasculitis and necrotizing herpetic keys,” Laboratory Animals,vol.42, no.2,pp.146–151, 1992. retinitis,” Investigative Ophthalmology & Visual Science,pp. 52– [39] F. Mitsunaga, S. Nakamura, T. Hayashi, and R. Eberle, “Changes 2975, 2011. in the titer of anti-B virus antibody in captive macaques [56] A. G. Freifeld, J. Hilliard, J. Southers et al., “A controlled (Macaca fuscata, M. mulatta, M. fascicularis),” Comparative seroprevalence survey of primate handlers for evidence of Medicine, vol. 57, no. 1, pp. 120–124, 2007. asymptomatic herpes b virus infection,” The Journal of Infectious [40] F. P. Gay and M. Holden, “The herpes encephalitis problem, ii,” Diseases,vol.171,no. 4,pp.1031–1034,1995. The Journal of Infectious Diseases ,vol.53, no.3,pp. 287–303, [57] K. L. Craig, M. K. Hasan, D. L. Jackson et al., “A seminomadic population in Bangladesh with extensive exposure to macaques [41] J. D. Pimentel, “Herpes B virus – “B” is for Brebner: Dr. William does not exhibit high levels of zoonotic simian foamy virus Bartlet Brebner (1903-1932),” Canadian Medical Association infection,” Journal of Virology, vol. 89, no. 14, pp. 7414–7416, Journal,vol.178,no. 6,pp.734-734,2008. [42] A. B. Sabin, “Acute ascending myelitis following a monkey bite, [58] W.F.Johnston,J.Yeh,R.Nierenberg, andG.Procopio, with the isolation of a virus capable of reproducing the disease,” “Exposure to Macaque Monkey Bite,” The Journal of Emergency eTh JournalofExperimentalMedicine ,vol.59, no.2,pp. 115–136, Medicine,vol.49, no.5,pp. 634–637, 2015. [59] M. A. Schillaci, L. Jones-Engel, G. A. Engel et al., “Prevalence [43] Fatal Cercopithecine herpesvirus 1 (B virus) infection following of enzootic simian viruses among urban performance monkeys a mucocutaneous exposure and interim recommendations for in Indonesia,” Tropical Medicine & International Health,vol.10, worker protection, MMWR 47:1073-1076, 1083, 1998. no.12, pp.1305–1314,2005. [44] A. W. Artenstein, C. B. Hicks, B. S. Goodwin Jr., and J. K. [60] P. Gautret, B. Jesse, L. Dacheux et al., “Correction to: Rabies Hilliard, “Human infection with B virus following a needlestick in Nonhuman Primates and Potential for Transmission to injury,” ReviewsofInfectiousDiseases,vol.13,no.2,pp. 288–291, Humans: A Literature Review and Examination of Selected French National Data (PLoS Negl Trop Dis, 9, 5),” PLOS [45] D. S. Davenport, D. R. Johnson, G. P. Holmes, D. A. Jewett, S. C. Neglected Tropical Diseases, vol. 9, no. 5, Article ID e0003799, Ross, and J. K. Hilliard, “Diagnosis and management of human b virus (herpesvims simiae) infections in michigan,” Clinical Infectious Diseases,vol.19,no.1,pp. 33–41,1994. [61] G. A. Engel, C. T. Small, K. Soliven et al., “Zoonotic simian foamy virus in Bangladesh reflects diverse patterns of transmis- [46] W. L. Davidson and K. Hummeler, “B Virus Infection in Man,” sion and co-infection,” Emerging Microbes & Infections,vol.2, Annals of the New York Academy of Sciences,vol.85, no.3,pp. no.9,pp. e58–e58, 2013. 970–979, 1960. [47] G.P. Holmes,J.K.Hilliard,K.C.Klontzetal.,“Bvirus(Her- [62] A. Fuentes and S. Gamerl, “Disproportionate participation pesvirus simiae) infection in humans: Epidemiologic investiga- by age/sex classes in aggressive interactions between long- tion of a cluster,” Annals of Internal Medicine, vol. 112, no. 11, pp. tailed macaques (Macaca fascicularis) and human tourists at 833–839, 1990. Padangtegal monkey forest, Bali, Indonesia,” American Journal of Primatology,vol.66,no.2,pp. 197–204,2005. [48] K. Hummeler, W. L. Davidson, W. Henle, A. C. Laboc- cetta, and H. G. Ruch, “Encephalomyelitis due to infection [63] B. P. Wheatley, eTh Sacred Monkeys of Bali, Waveland Press, with Herpesvirus simiae (herpes B virus); a report of two Prospect Heights, IL, USA, 1999. fatal, laboratory-acquired cases,” eTh New England Journal of [64] L. E. Mease and K. A. Baker, “Monkey bites among US military Medicine,vol.261,no. 2,pp.64–68,1959. members, Afghanistan, 2011,” Emerging Infectious Diseases,vol. [49] F. P. Nagler and M. Klotz, “A fatal B virus infection in a 18, no. 10, pp. 1647–1649, 2012. person subject to recurrent herpes labialis,” Canadian Medical [65] N. J. Riesland and H. Wilde, “Expert Review of Evidence Bases Association Journal,pp.79–743,1958. for Managing Monkey Bites in Travelers,” Journal of Travel [50] J. M. M. Nsabimana, M. Moutschen, E. Thiry, and F. Meurens, Medicine, vol. 22, no. 4, pp. 259–262, 2015. Cahiers/Sante´, Infection humaine par le virus B du singe en [66] A.M. Bennett,M. J.Slomka,D.W.G.Brown,G.Lloyd,and M. Afrique. CahiersSante1,3-8,2008. Mackett, “Protection against herpes B virus infection in rabbits [51] R. J. Whitely, J. K. Hilliard, Cercopithecine herpesvirus (B with a recombinant vaccinia virus expressing glycoprotein D,” virus), In: D. M. Knipe, P. M. Howley (eds) Fields Virology, Journal of Medical Virology,vol.57, no.1,pp.47–56,1999. Lippincott Williams and Wilkins, Philadelphia, PA, USA, pp 2835-2848, 2001. [67] E. A. Boulter and D. P. Grant, “Latent infection of monkeys with B virus and prophylactic studies in a rabbit model of this [52] G. E. Breen, S. G. Lamb, and A. T. Otaki, “Monkey-bite disease,” Journal of Antimicrobial Chemotherapy,vol.3,pp.107– encephalomyelitis report of a case—with recovery,” British 113, 1977. Medical Journal,vol.2,no. 5087,pp. 22-23,1958. [53] B. L. Bryan, C. D. Espana, R. W. Emmons, N. Vijayan, and [68] E. A. Boulter, H. T. Zwartouw, and B. Thornton, “Postexposure P. D. Hoeprich, “Recovery from encephalomyelitis caused by immunoprophylaxis against B virus (herpesvirus simiae) infec- herpesvirus simiae: report of a case,” JAMA Internal Medicine, tion,”BritishMedicalJournal(ClinicalResearched.),vol.283,no. vol. 135, no. 6, pp. 868–870, 1975. 6305, p. 1495, 1981. 14 Advances in Virology [69] R. N. Hull and J. C. Nash, “Immunization against b virus human and simian sera induced by herpes simplex and related infection: Preparation of an experimental vaccine,” American simian viruses,” Journal of Virological Methods,vol.14,no.2,pp. Journal of Epidemiology,vol.71, no.1,pp. 15–28,1960. 99–109, 1986. [85] Y. Ueda, I. Tagaya, and K. Shiroki, “Immunological relationship [70] L. Perelygina, I. Patrusheva, H. Zurkuhlen, and J. K. Hilliard, “Characterization of B virus glycoprotein antibodies induced by between herpes simplex virus and B virus,” Archiv fur die Gesamte Virusforschung,vol.24,no.3,pp.231–244,1968. DNA immunization,” Archives of Virology,vol.147,no. 11, pp. 2057–2073, 2002. [86] E. A. Boulter, S. S. Kalter, R. L. Heberling, J. E. Guajardo, and T. L. Lester, “A comparison of neutralization tests for [71] G. Gosztonyi, D. Falke, and H. Ludwig, “Axonal and transsy- the detection of antibodies to Herpesvirus simiae (monkey B naptic (transneuronal) spread of Herpesvirus simiae (B virus) virus),” Laboratory Animals,vol.32,no.2,pp. 150–152,1982. in experimentally infected mice,” Histology and Histopathology, vol. 7, no.1,pp. 63–74, 1992. [87] R. Eberle, D. Black, and J. K. Hilliard, “Relatedness of glyco- proteins expressed on the surface of simian herpesvirus virions [72] G. Gosztonyi, D. Falke, and H. Ludwig, “Axonal-transsynaptic and infected cells to specific HSV glycoproteins,” Archives of spread as the basic pathogenetic mechanism in B virus infection Virology,vol.109,no. 3-4,pp.233–252,1989. of the nervous system.,” Journal of Medical Primatology,vol.21, no. 1, pp. 42-43, 1992. [88] R.D.Henkel,H.M.McClure,P.Krug,D.Katz,andJ.K.Hilliard, “Serological evidence of alpha herpesvirus infection in sooty [73] J. W. Ritchey, M. E. Payton, and R. Eberle, “Clinicopathological mangabeys,” Journal of Medical Primatology,vol.31, no.3,pp. characterization of monkey B virus (cercopithecine herpesvirus 120–128, 2002. 1) infection in mice,” Journal of Comparative Pathology,vol.132, [89] B. Roizman, “eTh Herpesviruses. Albert S. Kaplan, Ed. Aca- no. 2-3, pp. 202–217, 2005. demic Press, New York, 1973. xvi, 740 pp., illus. %1,” Science,vol. [74] K. M.Rogers,J.W.Ritchey,M.Payton, D. H.Black, andR. 184, no. 4143, pp. 1277-1278, 1974. Eberle, “Neuropathogenesis of herpesvirus papio 2 in mice [90] S.-W. Mou, J. K. Hilliard, C.-H. Song, and R. Eberle, “Compar- parallels infection with Cercopithecine herpesvirus 1 (B virus) ison of the primate alphaherpesviruses - I. Characterization of in humans,” JournalofGeneralVirology,vol.87, no.2,pp. 267– two Herpesviruses from spider monkeys and squirrel monkeys 276, 2006. and viral polypeptides synthesized in infected cells,” Archives of [75] D. Black, J. Ritchey, M. Payton, and R. Eberle, “Role of the Virology, vol. 91, no. 1-2, pp. 117–133, 1986. virion host shutoff protein in neurovirulence of monkey B virus [91] D. J. McGeoch, F. J. Rixon, and A. J. Davison, “Topics in (Macacine herpesvirus 1),” Virologica Sinica,vol.29,no.5,pp. herpesvirus genomics and evolution,” Virus Research,vol.117, 274–283, 2014. no.1,pp. 90–104,2006. [76] L. A. Brush, D. H. Black, K. A. McCormack et al., “Papiine her- [92] A. Severini, S. D. Tyler, G. A. Peters, D. Black, and R. Eberle, pesvirus 2 as a predictive model for drug sensitivity of Macacine “Genome sequence of a chimpanzee herpesvirus and its relation herpesvirus 1 (monkey B virus),” Comparative Medicine,vol.64, to other primate alphaherpesviruses,” Archives of Virology,vol. no. 5, pp. 386–393, 2014. 158, no. 8, pp. 1825–1828, 2013. [77] R. Eberle,L.K.Maxwell,S.Nicholson,D.Black,andL. Jones- [93] J. O. Wertheim, M. D. Smith, D. M. Smith, K. Scheffler, and Engel, “Genome sequence variation among isolates of monkey S. L. Kosakovsky Pond, “Evolutionary origins of human herpes B virus (Macacine alphaherpesvirus 1) from captive macaques,” simplex viruses 1 and 2,” Molecular Biology and Evolution,vol. Virology,vol.508,pp. 26–35, 2017. 31, no. 9, pp. 2356–2364, 2014. [78] E. A. Kurt-Jones, M. Chan, S. Zhou et al., “Herpes simplex [94] A.Arvin,G. Campadelli-Fiume,E.Mocarskietal.,“Human virus 1 interaction with Toll-like receptor 2 contributes to lethal herpesviruses: Biology, therapy, and immunoprophylaxis,” encephalitis,” Proceedings of the National Acadamy of Sciences of Human Herpesviruses: Biology, er Th apy, and Immunoprophy- the United States of America,vol.101,no. 5,pp.1315–1320,2004. laxis,pp. 1–1410,2007. [79] P.Lundberg,C.Ramakrishna,J.Brown et al., “ei Th mmune [95] J. K.Hilliard,R.Eberle, S.L. Lipper,R.M.Munoz,and S. response to herpes simplex virus type 1 infection in susceptible A. Weiss, “Herpesvirus simiae (B virus): Replication of the miceisamajorcauseof centralnervoussystempathology virus and identification of viral polypeptides in infected cells,” resulting in fatal encephalitis,” Journal of Virology,vol.82, no. Archives of Virology,vol.93, no.3-4,pp.185–198,1987. 14, pp. 7078–7088, 2008. [96] R. N. Hull, “B virus vaccine,” Laboratory Animal Science,vol.21, [80] K.M. Rogers,K.A.Ealey,J.W.Ritchey,D.H.Black,andR. pp. 1068–1071, 1971. Eberle, “Pathogenicity of different baboon Herpesvirus papio [97] K.Ohsawa,D.H.Black,H.Sato, andR.Eberle, “Sequence 2 isolates is characterized by either extreme neurovirulence or and genetic arrangement of the Us region of the monkey B complete apathogenicity,” JournalofVirology,vol.77, no.20, pp. virus (Cercopithecine Herpesvirus 1) genome and comparison 10731–10739, 2003. with the Us regions of other primate herpesviruses,” Journal of [81] B. V. Troan, L. Perelygina, I. Patrusheva et al., “Naturally Virology,vol.76,no.3,pp.1516–1520, 2002. transmitted herpesvirus papio-2 infection in a black and white [98] K. Ohsawa,D.H.Black,H.Sato, K.Rogers,andR. Eberle, colobus monkey,” Journal of the American Veterinary Medical “Sequence and genetic arrangement of the UL region of the Association,vol.231,no. 12,pp.1878–1883, 2007. monkey B virus (Cercopithecine herpesvirus 1) genome and [82] R. Eberle and J. Hilliard, “eTh simian herpesviruses,” Infectious comparison with the UL region of other primate herpesviruses,” Agents and Disease, vol. 4, no. 2, pp. 55–70, 1995. Archives of Virology,vol.148,no. 5,pp.989–997,2003. [83] J. K.Hilliard,D.Black,andR. Eberle,“Simian alphaher- [99] L. Perelygina,L.Zhu,H.Zurkuhlen,R.Mills,M. Borodovsky, pesviruses and their relation to the human herpes simplex andJ.K.Hilliard,“Completesequenceandcomparativeanalysis viruses,” Archives of Virology,vol.109,no. 1-2, pp.83–102,1989. of the genome of herpes B virus (Cercopithecine herpesvirus 1) [84] D. Katz,J.K.Hilliard,R.Eberle,andS.L.Lipper,“ELISA for from a rhesus monkey,” Journal of Virology,vol.77,no.11, pp. detection of group-common and virus-specific antibodies in 6167–6177, 2003. Advances in Virology 15 [100] K. Ohsawa, D. Black, M. Ohsawa, and R. Eberle, “Genome [115] G. L. Van Hoosier Jr. and J. L. Melnick, “Neutralizing antibodies sequence of a pathogenic isolate of monkey B virus (species in human sera to Herpesvirus simiae (B virus),” Texas Reports Macacine herpesvirus 1),” Archives of Virology,vol.159,no.10, on Biology and Medicine,vol.19, pp.376–380,1961. pp.2819–2821,2014. [116] D. Katz, W. Shi, M. S. Gowda et al., “Identification of unique B virus (Macacine Herpesvirus 1) epitopes of zoonotic and [101] K. Ohsawa, D. H. Black, R. Torii, H. Sato, and R. Eberle, “Detec- tion of a unique genotype of monkey B virus (Cercopithecine macaque isolates using monoclonal antibodies,” PLoS ONE,vol. herpesvirus 1) indigenous to native Japanese macaques (Macaca 12, no. 8, Article ID e0182355, 2017. fuscata),” Comparative Medicine,vol.52,no.6,pp.555–559, [117] I. Patrusheva, L. Perelygina, I. Torshin, J. LeCher, and J. Hilliard, “B virus (Macacine herpesvirus 1) divergence: Variations in glycoprotein D from clinical and laboratory isolates diversify [102] A.L.Smith,D.H.Black,andR. Eberle,“Molecularevidence virus entry strategies,” Journal of Virology,vol.90, no.20,pp. for distinct genotypes of monkey B virus (herpesvirus simiae) 9420–9432, 2016. which are related to the macaque host species,” Journal of Virology, vol. 72, no. 11, pp. 9224–9232, 1998. [118] E. Linwood Blewett, J. T. Saliki, and R. Eberle, “Development of a competitive ELISA for detection of primates infected with [103] M. A. Amen and A. Griffiths, “Identification and expression monkey B virus (Herpesvirus simiae),” JournalofVirological analysis of herpes B virus-encoded small RNAs,” Journal of Methods,vol.77,no.1,pp. 59–67, 1999. Virology, vol. 85, no. 14, pp. 7296–7311, 2011. [119] L. M. Cropper,D.N.Lees, R. Patt,I.R.Sharp,andD. Brown, [104] M. I. Besecker, M. E. Harden, G. Li, X.-J. Wang, and A. Gritffi hs, “Monoclonal antibodies for the identification of herpesvirus “Discovery of herpes B virus-encoded MicroRNAs,” Journal of simiae (B virus),” Archives of Virology,vol.123,no. 3-4,pp.267– Virology,vol.83,no.7,pp.3413–3416,2009. 277, 1992. [105] S. D. Tyler, G. A. Peters, and A. Severini, “Complete genome [120] H. P. Huemer, C. Wechselberger, A. M. Bennett, D. Falke, and L. sequence of cercopithecine herpesvirus 2 (SA8) and compari- Harrington, “Cloning and expression of the complement recep- son with other simplexviruses,” Virology,vol.331,no.2,pp.429– tor glycoprotein C from Herpesvirus simiae (herpes B virus): 440, 2005. Protection from complement-mediated cell lysis,” Journal of [106] S. D. Tyler and A. Severini, “The complete genome sequence General Virology,vol.84, no.5,pp. 1091–1100, 2003. of herpesvirus papio 2 (Cercopithecine herpesvirus 16) shows [121] Q.Fan,M.Amen, M. Harden,A.Severini,A.Gritffi hs,andR. evidence of recombination events among various progenitor Longnecker, “Herpes B virus utilizes human nectin-1 but not herpesviruses,” Journal of Virology,vol.80,no.3,pp.1214–1221, HVEM or PILR𝛼 for cell-cell fusion and virus entry,” Journal of Virology,vol.86,no.8,pp. 4468–4476, 2012. [107] R. Eberle and D. H. Black, Molecular aspects of monkey B virus [122] L. Li, Z. Qiu, Y. Li et al., “Herpes B virus gD interaction with and implications for diagnostic test development, Recent Res itshumanreceptor-Aninsilicoanalysisapproach,” Theoretical Devel Virol, vol. 1, pp. 85-94, 1999. Biology and Medical Modelling,vol.11,no.1,article no.27, 2014. [108] L. Perelygina, H. Zurkuhlen, I. Patrusheva, and J. K. Hilliard, [123] C.Boutell andR.D.Everett,“Regulationof alphaherpesvirus “Identification of a herpes B virus-specific glycoprotein D infections by the ICP0 family of proteins,” Journal of General immunodominant epitope recognized by natural and foreign Virology,vol.94,no.3,pp. 465–481,2013. hosts,” The Journal of Infectious Diseases ,vol.186,no. 4,pp.453– [124] K.M.Rogers, R. F.Wolf,G.L.White,and R.Eberle,“Experi- 461, 2002. mental infection of baboons (Papio cynocephalus anubis) with [109] L.Perelygina, I.Patrusheva,S.Hombaiahetal.,“Production apathogenic and neurovirulent subtypes of Herpesvirus papio of herpes B virus recombinant glycoproteins and evaluation of 2,” Comparative Medicine,vol.55, no.5,pp. 425–430, 2005. their diagnostic potential,” Journal of Clinical Microbiology,vol. [125] D.Black,K.Ohsawa, S.Tyler, L.Maxwell, andR.Eberle, “A 43,no. 2,pp.620–628,2005. single viral gene determines lethal cross-species neurovirulence [110] M. J.Slomka,L.Harrington,C. Arnold,J.P.N.Norcott, of baboon herpesvirus HVP2,” Virology,vol.452-453,pp.86–94, andD.W.G.Brown,“Complete nucleotidesequence ofthe herpesvirus simiae glycoprotein G gene and its expression as [126] T. Todo, “Active immunotherapy oncolytic virus therapy using an immunogenic fusion protein in bacteria,” Journal of General Virology,vol.76,no.9,pp. 2161–2168,1995. HSV-1,” Advances in Experimental Medicine and Biology,vol. 746,pp.178–186,2012. [111] K. Tanabayashi, R. Mukai, and A. Yamada, “Detection of B virus [127] J. Conner, J. Macfarlane, H. Lankinen, and H. Marsden, “eTh antibody in monkey sera using glycoprotein D expressed in unique N terminus of the herpes simplex virus type 1 large mammalian cells,” Journal of Clinical Microbiology,vol.39, no. subunit is not required for ribonucleotide reductase activity,” 9, pp. 3025–3030, 2001. Journal of General Virology, vol. 73, no. 1, pp. 103–112, 1992. [112] R. L. Heberling and S. S. Kalter, “A dot-immunobinding assay [128] D. Lembo and W. Brune, “Tinkering with a viral ribonucleotide on nitrocellulose with psoralen inactivated Herpesvirus simiae reductase,” Trends in Biochemical Sciences,vol.34,no.1,pp.25– (B virus).,” Laboratory animal science Chicago,vol.37, no.3,pp. 32, 2009. 304–308, 1987. [129] H.Guo,S.Omoto,P.A.Harrisetal.,“Herpessimplexvirus [113] D. Katz, W. Shi, P. W. Krug, R. Henkel, H. McClure, and J. suppresses necroptosis in human cells,” Cell Host & Microbe,vol. K. Hilliard, “Antibody cross-reactivity of alphaherpesviruses as 17,no.2, pp.243–251,2015. mirrored in naturally infected primates,” Archives of Virology, vol. 147, no. 5, pp. 929–941, 2002. [130] Z. Huang, S.-Q. Wu, Y. Liang et al., “RIP1/RIP3 binding to HSV-1 ICP6 initiates necroptosis to restrict virus propagation [114] D. Katz,W.Shi,P.W.Krug, andJ.K.Hilliard,“Alphaherpesvirus in mice,” Cell Host & Microbe,vol.17, no.2,pp.229–242, 2015. antigen quantitation to optimize the diagnosis of herpes B virus infection,” JournalofVirological Methods,vol.103,no.1,pp.15– [131] X. Wang, Y. Li, S. Liu et al., “Direct activation of RIP3/MLKL- 25, 2002. dependent necrosis by herpes simplex virus 1 (HSV-1) protein 16 Advances in Virology ICP6 triggers host antiviral defense,” Proceedings of the National infection with𝛾134.5- mutants of herpes simplex virus,” Pro- Acadamy of Sciences of the United States of America, vol. 111, no. ceedings of the National Acadamy of Sciences of the United States 43, pp. 15438–15443, 2014. of America,vol.92,no.23, pp.10516–10520,1995. [132] C. A. Bolovan, N. M. Sawtell, and R. L. o Th mpson, “ICP34.5 [145] P.A.M.GobeilandD. A.Leib,“Herpes simplexvirus mutants of herpes simplex virus type 1 strain 17syn+ are gamma34.5 interferes with autophagosome maturation and attenuated for neurovirulence in mice and for replication in antigen presentation in dendritic cells,” mBio,vol.3,no. 5,pp. confluent primary mouse embryo cell cultures,” Journal of e00267–e00212, 2012. Virology,vol.68,no.1,pp.48–55,1994. [146] B. He, M. Gross, and B. Roizman, “The 𝛾134.5 protein of [133] J.Chou,E.R.Kern,R.J.Whitley, andB.Roizman,“Mapping herpes simplex virus 1 complexes with protein phosphatase 1𝛼 of herpes simplex virus-1 neurovirulence to 𝛾134.5, a gene to dephosphorylate the𝛼 subunit of the eukaryotic translation nonessential for growth in culture,” Science,vol.250,no. 4985, initiation factor 2 and preclude the shutoff of protein synthesis pp. 1262–1266, 1990. by double-stranded RNA-activated protein kinase,” Proceedings of the National Acadamy of Sciences of the United States of [134] L. Y. Lee and P. A. Schaer ff , “A virus with a mutation in the ICP4-binding site in the L/ST promoter of herpes simplex virus America, vol. 94, no. 3, pp. 843–848, 1997. type 1, but not a virus with a mutation in open reading frame P, [147] B. He, M. Gross, and B. Roizman, “The 𝛾134.5 Protein of herpes exhibits cell-type-specific expression of 𝛾134.5 transcripts and simplex virus I has the structural and functional attributes of a latency-associated transcripts,” Journal of Virology,vol.72, no. protein phosphatase I regulatory subunit and is present in a high 5, pp. 4250–4264, 1998. molecular weight complex with the enzyme in infected cells,” [135] N. S. Markovitz, D. Baunoch, and B. Roizman, “The range and The Journal of Biological Chemistry ,vol.273,no.33,pp. 20737– distribution of murine central nervous system cells infected 20743, 1998. with the𝛾134.5-Mutantofherpessimplex virus1,” Journal of [148] A. Simmons and A. A. Nash, “Zosteriform spread of herpes Virology,vol.71, no.7,pp. 5560–5569, 1997. simplex virus as a model of recrudescence and its use to [136] B. Roizman and N. Markovitz, “Herpes simplex virus virulence: investigate the role of immune cells in prevention of recurrent the functions of the gamma (1)34.5 gene,” Journal of NeuroVirol- disease,” Journal of Virology,vol.52,no.3,pp. 816–821,1984. ogy,vol.3Suppl,p. S1,1997. [149] Y. Tsalenchuck, T. Tzur, I. Steiner, and A. Panet, “Different [137] R. J. Whitley, E. R. Kern, S. Chatterjee, J. Chou, and B. Roizman, modes of herpes simplex virus type 1 spread in brain and skin “Replication, establishment of latency, and induced reactivation tissues,” Journal of NeuroVirology,vol.20,no.1,pp. 18–27,2014. of herpes simplex virus 𝛾1 34.5 deletion mutants in rodent [150] L. M. Wakim, C. M. Jones, T. Gebhardt, C. M. Preston, and F. R. models,” eTh Journal of Clinical Investigation ,vol.91, no.6,pp. Carbone, “CD8+ T-cell attenuation of cutaneous herpes simplex 2837–2843, 1993. virus infection reduces the average viral copy number of the [138] D. Phelan, E. R. Barrozo, and D. C. Bloom, “HSV1 latent ensuing latent infection,” Immunology & Cell Biology,vol.86, transcription and non-coding RNA: A critical retrospective,” no.8,pp.666–675,2008. Journal of Neuroimmunology,vol.308,pp. 65–101,2017. [151] M. Yamada, Y. Arao, F. Uno, and S. Nii, “Mechanism of Differ- [139] G. Cheng, M.-E. Brett, and B. He, “Val193 and Phe195 of the ences in Pathogenicity between Two Variants of a Laboratory 𝛾134.5 protein of herpes simplex virus 1 are required for viral Strain of Herpes Simplex Virus Type 1,” Microbiology and resistance to interferon-𝛼/𝛽,” Virology,vol.290,no. 1, pp.115– Immunology, vol. 30, no. 12, pp. 1259–1270, 1986. 120, 2001. [152] Y. Minamishima and Y. Eizuru, “Susceptibility of Primate [140] X. Jing, M. Cerveny, K. Yang, and B. He, “Replication of herpes Diploid Cells to Human Herpesviruses,” Microbiology and simplex virus 1 depends on the𝛾134. 5 functions that facilitate Immunology, vol. 21, no. 11, pp. 667–671, 1977. virus response to interferon and egress in the different stages [153] S. Nii, “Abortive infection of LLC-MK2 cells by Herpes simplex of productive infection,” Journal of Virology, vol. 78, no. 14, pp. virus.,” Biken Journal, Journal of the Research Institute for 7653–7666, 2004. Microbial Diseases,vol.15, no.1,pp. 43–47, 1972. [141] J. Trgovcich, D. Johnson, and B. Roizman, “Cell surface major [154] M. Yamada, “Replication of herpes simplex virus in two cell histocompatibility complex class II proteins are regulated by the systems derived from rhesus monkeys,” Biken Journal, Journal products of the𝛾34.5 and UL41 genes of herpes simplex virus 1,” of the Research Institute for Microbial Diseases,vol.26,no.1,pp. Journal of Virology, vol. 76, no. 14, pp. 6974–6986, 2002. 35–47, 1983. [142] J. Chou and B. Roizman, “eTh 𝛾134.5 gene of herpes simplex [155] L. Perelygina, I. Patrusheva, M. Vasireddi, N. Brock, and J. virus 1 precludes neuroblastoma cells from triggering total Hilliard, “Virus (Macacine herpesvirus 1) glycoprotein D is shutoff of protein synthesis characteristic of programed cell functional but dispensable for virus entry into macaque and death in neuronal cells,” Proceedings of the National Acadamy of humanskincells,” Journal of Virology,vol.89,no.10, pp.5515– Sciences of the United States of America,vol.89,no.8,pp.3266– 5524, 2015. 3270, 1992. [156] M. L. van de Weijer, R. D. Luteijn, and E. J. H. J. Wiertz, “Viral [143] J. Chou and B. Roizman, “Herpes simplex virus 1𝛾134.5 gene immune evasion: Lessons in MHC class I antigen presentation,” function, which blocks the host response to infection, maps in Seminars in Immunology,vol.27,no.2,pp.125–137,2015. the homologous domain of the genes expressed during growth arrest and DNA damage,” Proceedings of the National Acadamy [157] M. Vasireddi and J. Hilliard, “Herpes B virus, macacine her- pesvirus 1, breaks simplex virus tradition via major histocom- of Sciences of the United States of America,vol.91,no.12,pp. 5247–5251, 1994. patibility complex class I expression in cells from human and macaque hosts,” Journal of Virology,vol.86,no.23,pp.12503– [144] J. Chou, J.-J. Chen, M. Gross, and B. Roizman, “Association of 12511, 2012. a Mr 90,000 phosphoprotein with protein kinase PKR in cells exhib [158] M. Vasireddi and J. K. Hilliard, “Regulation of PI3K/Akt iting enhanced phosphorylation of translation initiation factor eIF-2𝛼 and premature shutoff of protein synthesis after dependent apoptotic markers during b virus infection of human Advances in Virology 17 and macaque fibroblasts,” PLoS ONE,vol.12, no.5,ArticleID e0178314, 2017. [159] B. Roizman, G. Zhou, and T. Du, “Checkpoints in productive and latent infections with herpes simplex virus 1: conceptual- ization of the issues.,” Journal of NeuroVirology,vol.17, no.6, pp.512–517,2011. [160] B.Roizman andR.J.Whitley,“Aninquiryintothemolecular basis of HSV latency and reactivation,” Annual Review of Microbiology,vol.67,pp.355–374,2013. [161] S. Efstathiou and C. M. Preston, “Towards an understanding of themolecular basisofherpessimplexviruslatency,” Virus Research, vol. 111, no. 2, pp. 108–119, 2005. [162] W.A.Blyth,D.A.Harbour,and T. J. Hill,“Pathogenesisof zosteriform spread of herpes simplex virus in the mouse,” Journal of General Virology,vol.65,no.9,pp.1477–1486,1984. [163] B. Roizman and G. Zhou, “eTh 3 facets of regulation of herpes simplex virus gene expression: A critical inquiry,” Virology,vol. 479-480, pp. 562–567, 2015. [164] T. Kramer and L. W. Enquist, “Directional spread of alphaher- pesviruses in the nervous system,” Viruses,vol.5,no.2,pp.678– 707, 2013. 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Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1)

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Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1)

Questioning the Extreme Neurovirulence of Monkey B Virus (Macacine alphaherpesvirus 1)

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