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Assessing the differential impact of chronic CMV and treated HIV infection on CD8+ T-cell differentiation in a matched cohort study: is CMV the key?

Assessing the differential impact of chronic CMV and treated HIV infection on CD8+ T-cell... Background: Cytomegalovirus (CMV ) infection is one of the main driving forces of T‑ cell senescence in the gen‑ eral population, whereas its differential impact in people living with HIV (PLWH) is less well characterized. The study explores the effect of latent CMV infection on T ‑ cell subsets, monocyte/macrophages activation markers, and CRP in PLWH on long‑term ART. Methods: Cross‑sectional cohort study including PLWH on long‑term suppressive ART. Individuals of 4 groups (HIV+CMV−, HIV+CMV+, HIV−CMV+, and HIV−CMV−) were matched 1:1:1:1 for age and sex. Immunophenotyping of lymphocyte and T‑ cell subsets by multicolor flow cytometry was performed in fresh blood samples collected from patients and healthy donors. Results: Both, latent CMV and treated HIV infection were associated with an expansion of CD8 T cells, a reduced CD4/CD8 ratio, and with CD8 T‑ cell activation with a cumulative effect in CMV/HIV ‑ coinfected individuals. CMV was associated with elevated numbers of late effector and terminally differentiated CD8 T ‑ cells. Compared to CMV mono‑ infection, CMV/HIV coinfection showed to be associated with lower proportion of CD28−CD8+ T cells expressing CD57 suggesting that HIV preferentially expands CD28−CD57−CD8+ T cells and impedes terminal differentiation of CD28−CD8+ T cells. We could not show any association between HIV or CMV infection status and concentration of CRP and CD163. Conclusions: CMV infection is associated with phenotypic signs of T‑ cell senescence, promoting exacerbation and persistence of alterations of the T‑ cell compartment in PLWH on effective ART, which are associated with adverse clini‑ cal outcomes and may be an attractive target for therapeutic interventions. Keywords: HIV, CMV, T‑ cell senescence, CD163, CRP, Inflammation Background Antiretroviral therapy (ART) led to a remarkable improvement in long-term life-expectancy of people liv- ing with HIV (PLWH) [1]. Despite treatment-mediated *Correspondence: matthias.mueller@uniklinik‑freiburg.de continuous suppression of HIV replication and consecu- Division of Infectious Diseases, Department of Medicine II, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, tive restoration of CD4 cell count, PLWH retain a higher Hugstetter Straße 55, 79106 Freiburg, Germany risk for death and aging-related disorders including Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mueller et al. AIDS Res Ther (2021) 18:37 Page 2 of 9 cardiovascular, renal, liver, neurologic, and bone disease prevalence in the general population increases with age [2]. Because HIV induces immunologic dysfunctions and is 55% among blood donors in Germany, whereas the showing similarities to those observed in elderly popula- CMV prevalence in HIV cohorts generally is about 90% tions, it has been hypothesized that HIV-induced accel- independent of age [20, 21]. erated aging of the immune system (immune senescence) To evaluate the differential effect of CMV and HIV could mediate these risks. infection on markers of immune dysfunction, we per- T-cell senescence, whether driven by aging and/or by formed a cohort study matching for sex and age CMV- chronic antigenic stimulation from pathogens such as negative and -positive individuals with and without HIV HIV or cytomegalovirus (CMV), is typically character- infection. ized by T-cell activation, inversion of the CD4/CD8 ratio due to low CD4 T-cell counts and accumulation of ter- Methods minally differentiated CD8 T cells with shortened telom - Ethics consideration eres, a decrease in the costimulatory molecule CD28, and The study was approved by the institutional ethics review increased expression of CD57, a marker of proliferative board of the medical center of the University of Freiburg history and poor proliferative capacity [3, 4]. (No.: 317/15, Date: 31 July 2015). All PLWH  were Markers of inflammation like c-reactive protein (CRP) recruited at the HIV Centre Freiburg and provided writ- and of monocyte/macrophage activation, like soluble ten informed consent. Blood donors provided informed CD14 (sCD14) and soluble CD163 (sCD163), have been consent for the scientific use of surplus portions of their shown to be elevated in HIV infection and to be asso- blood donation. ciated with the risk for non-AIDS-defining morbidity, especially with cardiovascular disease [5–11]. Study design/setting In PLWH, ART improves many of these HIV-induced This cross-sectional cohort study was carried out at the immunologic alterations, but the effect is incomplete, HIV Centre Freiburg, Germany, caring for about 800 and markers of immune activation, inflammation and PLWH. Patients were enrolled between November 26, T-cell differentiation remain altered. The mechanism 2015 and November 23, 2016. Because CMV seronega- inducing residual immune dysfunction is complex and tive PLWH are rare, patient records of PLWH attending multifactorial in origin. Chronic coinfection with CMV the HIV Centre Freiburg were screened for CMV seron- has been identified to strongly contribute to persistent egative patients. Blood samples were taken at enrollment immune activation, to be associated with lower CD4/ of patients and CMV serostatus was reassessed using a CD8 T-cell ratios, with reduced expression of CD28 and CMV immunoglobulin G (IgG) assay (Abbott Architect increased expression of CD57 in PLWH people with HIV CMV IgG CLIA, Abbott Diagnostics, Wiesbaden, Ger- on long term ART [3, 12–14]. many). HIV-infected CMV-seronegative patients were Differences in alterations of T-cell compartments then matched 1:1:1:1 for sex and age with HIV-infected, between HIV infection on one side and CMV monoin- CMV-seropositive patients and with HIV-uninfected, fection and aging on the other side may exist. In a study CMV-seropositive and CMV-seronegative blood donors of Lee and colleagues, CMV infection and aging were from the Blood Donation Center Freiburg. associated with high proportions CD28−CD8+ T-cells HIV-infected patients were eligible when they were expressing CD57, whereas PLWH showed an enrich- on ART with ≥ 12  months of HIV RNA < 20  cp/ml. ment of less well-differentiated transitional CD8+ T cells Exclusion criteria for HIV-infected patients were active and abnormally low proportions of CD28−CD8+ T cells Hepatitis B or Hepatitis C, untreated sexual transmitted expressing CD57. In a consecutive study, the authors disease (syphilis, gonorrhea, and Chlamydia trachomatis could show that low proportions of CD28−CD8+ T cells infection), previous or current CMV-related organ dis- expressing CD57 strongly predicted increased all-cause eases, organ transplantation, as well as cancer or treat- mortality in PLWH under ART [15, 16]. These studies ment of cancer, autoimmune disease with or without use however did not assess the effect of CMV coinfection on of immunosuppressive or immunomodulant drugs in the the magnitude of CD57 expression of CD28−CD8+ T previous 5 years. cells and on clinical outcome. Equally, many other studies assessing the HIV-induced Study diagnostic procedures effects on immune senescence did not control for CMV Lymphocyte and T‑cell subpopulations phenotyping coinfection and/or did not employ HIV-negative indi- Phenotyping of T-, B- and NK cells within the lympho- viduals, making it impossible to discriminate the effects cyte population as well as T-cell subpopulations was per- of CMV and HIV on the immune dysfunction perceived formed by a whole blood staining lyse-no wash protocol in PLWH on long term ART [3, 12–14, 17–19]. CMV (Optilyse B, Beckman-Coulter) using six colour flow M ueller et al. AIDS Res Ther (2021) 18:37 Page 3 of 9 cytometry with fluorochrome-conjugated antibodies as Results listed in Additional file 1: Table S1. A total of 92 patients were included in the study, form- Antibody labelled cells were analyzed by flow cytom - ing 23 sets with each 4 matched individuals. Median age etry (Navios; Beckman Coulter). Absolute cell counts was 49.4  years [interquartile range (IQR), 44.3–54.3] were calculated using a two platform method with leu- and 30.4% of participants were women without differ - cocyte and lymphocyte counts determined by a hemo- ences between the 4 groups (Table  1). Median time of cytometer. Flow cytometric data analysis was performed HIV RNA below limit of detection was 64 months (IQR, with the help of Kaluza Software 1.5a (Beckman Coulter). 20–96) in HIV+CMV+ and 62 months (IQR, 15–108) in Representative gating strategies for analysed populations HIV+CMV− patients. are shown in Additional file  2: Figure S1 and Additional file 3: Figure S2. Lymphocyte and T‑cell subpopulations phenotyping As expected, lymphocyte subpopulation analysis revealed lower amounts of CD4+ T cells in HIV infected indi- sCD163 and CRP analysis HIV+CMV+ HIV− viduals (median = 469.5/µl versus me dian sCD163 concentrations in cryopreserved plasma samples CMV+ HIV+CMV− = 825.0/µl; p = 0.0049 and median = 564/ were quantified by using a commercially available ELISA HIV−CMV− µl versus median = 758.0/µl; p = 0.0115) but kit (Quantikine, R&D Systems, Minneapolis, MN, United there was no significant difference between the CMV+ States of America). All samples were tested in duplicate. and CMV− groups both in PLWH and healthy controls hsCRP concentrations in cryopreserved plasma sam- (Fig.  1A). The further analysis revealed higher absolute ples were quantified by using the standard immunotur - numbers of CD8+ T cells in CMV+ patients both in bidometric assay on the COBAS INTEGRA system HIV+CMV+ the HIV− and HIV+ groups (median = 700/ (Roche COBAS INTEGRA, Roche Diagnostics, Basel HIV+CMV− µl versus me dian = 491.5/µl, p = 0.0102 Switzerland). HIV−CMV+ HIV− and median = 482.0/µl versus median CMV− = 306/µl, p = 0.0002; Fig.  1B) and a significantly Statistical analysis lower CD4/CD8 ratio in CMV+ subjects both in the HIV+CMV+ A Kruskal–Wallis test was conducted to determine if HIV− and HIV+ groups (me dian = 0.74 ver- HIV+CMV− HIV− levels of CRP and sCD163 were statistically different sus median = 1.32, p = 0.0006 and me dian CMV+ HIV−CMV− between the four cohorts. Spearman’s rank correlation = 1.67 versus median = 2.93; p = 0.0023, coefficient was calculated to determine associations Fig. 1C). between variables. For pairwise statistical analysis of flow cytometric two sided Wilcoxon matched-pairs signed T‑cell subpopulations phenotyping rank test (analyzed data showed a non-Gaussian dis- For analysis of T-cell activation markers, HLA-DR was tribution) was performed for cell counts of individual counterstained and analyzed on CD3+, CD4+ and cell populations. Normality testing was done using the CD8+ T cells. This showed higher absolute numbers D’Agostino & Pearson normality test. Statistical results of CD8+HLA−DR+ T cells in CMV+ patients both in HIV+CMV+ were calculated with the of Graphpad Prism Software the HIV− and HIV+ groups (median = 118/ HIV+CMV− version 8 (Graphpad Software, San Diego, USA). µl versus median = 71/µl, p = 0.0176 and Table 1 Baseline characteristics of participating patients matched for sex and age recruited from a HIV cohort between November 2015 and November 2016 Total HIV+ HIV− CMV+ CMV− CMV+ CMV− n 92 23 23 23 23 Female, n (%) 28 (30.4) 7 (30.4) 7 (30.4) 7 (30.4) 7 (30.4) Age (y), median (IQR) 49.4 (44.3–54.3) 50.1 (44.3–54.3) 48.6 (44.3–54.0) 49.4 (44.1–55.4) 49.5 (45.2–55.0) Time since HIV infection (y), median (IQR) 14.5 (6.6–21.0) 12.5 (6.6–19.7) 17.1 (6.5–23.1) NA NA CD4 nadir (cells/µl), median (IQR) 190.5 (95.0–255.0) 197.0 (95.0–257.0) 173.5 (95.0–223.0) NA NA VL < LoD (months), median (IQR) 63.0 (20.0–99.0) 64.0 (20.0–96.0) 62.0 (15.0–108.0) NA NA CD4, (cells/µl), median (IQR) NA 469.5 (364.5–635.3) 564.0 (380.8–727.3) 825.0 (584.8–1054.0) 758.0 (593.0–1045.0) VL viral load, LoD limit of detection, y year, ART antiretroviral therapy, CMV cytomegalovirus, NA not applicable, IQR interquartile range Mueller et al. AIDS Res Ther (2021) 18:37 Page 4 of 9 Fig. 1 Lymphocyte subsets and activated T cells. A Absolute counts of CD4+ T cells/µl. B absolute counts of CD8+ T cells/µl. C CD4/CD8 ratio. Black horizontal lines correspond to the median and errors bars show the interquartile ranges. Red circles: HIV positive and CMV negative individual; red squares: HIV positive and CMV positive individual; blue circles: HIV negative and CMV negative individual; blue squares: HIV negative and CMV positive individual HIV−CMV+ HIV−CMV− median = 51/µl versus me dian = 37/ 437.0–634.0  ng/ml) and HIV−CMV−: 609  ng/ml µl, p = 0.0072; Fig. 2A). (IQR, 472.0–695.0  ng/ml), p = 0.9208] (Fig .  3). Corre- Naïve CD4+CD45RA+ T cells were lower in absolute lation analysis showed that sCD163 levels were posi- numbers in HIV+CMV+ patients when compared to tively correlated with age in the group of CMV+HIV+ HIV+CMV+ CMV+ healthy controls (median = 151/µl ver- (r = 0.49, p = 0.020) and in CMV+HIV− with border- HIV−CMV+ sus median = 339/µl, p = 0.0083) (Fig.  2B). The line statistical significance (r = 0.63, p = 0.062) but expanded CD8+ T-cell subset of CMV+ subjects was not in CMV− subgroups (CMV−HIV−: r = − 0.146, enriched for CD8+CD27−CD28− early and late effector p = 0.529; CMV−HIV+: r = 0.257, p = 0.274). We could HIV+CMV+ cells in HIV+ and HIV− groups (median = 269/ neither detect an association between sCD163 levels HIV+CMV− µl versus median = 36.5/µl, p < 0.0001 and and duration of HIV infection (CMV+HIV+: r = 0.311, HIV−CMV+ HIV−CMV− median = 134/µl versus median = 14/ p = 0.159; CMV−HIV+: r = 0.298, p = 0.202) nor µl; p < 0.0001) (Fig.  2C, D) and CD8+CD57+ termi- with CD4 Nadir (CMV+HIV+: r = − 0.181, p = 0.593; HIV+CMV+ nally differentiated CD8 T cells (median = 206/ CMV−HIV+: r = 0.128, p = 0.709) or current CD4 cell HIV+CMV− µl versus me dian = 77.5/µl; p = 0.0011 and count (CMV+HIV+: r = − 0.018, p = 0.9377; CMV− HIV−CMV+ HIV−CMV− median = 155/µl versus median = 49/ HIV+: r = 0.104, p = 0.6633). µl, p < 0.0001) (Fig.  2E). Within the CD8+CD28− In the 17 quadruples with available CRP concentra- T-cell subset the increase of CD57+ cells was even tion measurement of all four individuals the median HIV+CMV+ more significant (median = 200/µl versus CRP concentration was 1.2  mg/l (IQR, 0.7–3.0  ng/ HIV+CMV− HIV− median = 65.5/µl; p = 0.0003 and me dian ml), without differences between the four sub - CMV+ HIV−CMV− = 135/µl versus median = 29/µl, groups [HIV+CMV+: 1.6  mg/l (IQR, 1.0–3.5  mg/l), p < 0.0001) (Fig. 2F). HIV+CMV−: 1.2  mg/l (IQR, 0.7–2.25  mg/l), HIV− CMV+: 1.2 mg/l (IQR, 0.8–2.5 mg/l) and HIV−CMV−: 1.1 mg/l (IQR, 0.7–3.0 mg/l), p = 0.684] (Fig . 3). Markers of inflammation and monocyte activation In the 17 quadruples with available sCD163 con- centration measurement of all four patients the Discussion median sCD163 concentration was 555  ng/ml (IQR, To our knowledge, this is the first study showing the 408.0–733.5  ng/ml), without differences between differential impact of CMV infection and treated HIV the four subgroups [HIV+CMV+: 628  ng/ml (IQR, infection on T-cell subpopulations. 360.0–822.0  ng/ml), HIV+CMV−: 540  ng/ml (IQR, 396.0–725.0  ng/ml), HIV−CMV+: 520  ng/ml (IQR, M ueller et al. AIDS Res Ther (2021) 18:37 Page 5 of 9 Fig. 2 CD4+ and CD8+ T‑ cell subpopulations. A Absolute counts of CD8+ HLA‑DR+ T cells/µl. B Absolute counts of CD4+CD45RA+ naïve T cells/ µl. C absolute counts of CD8+CD28+ CD27− early effector T cells/µl. D Absolute counts CD8+CD28−CD27− late effector T cells/µl. E Absolute counts CD8+CD57+ terminally differentiated T cells/µl. F Absolute counts CD8+CD28−CD57+ terminally differentiated T cells/µl. Black horizontal lines correspond to the median and errors bars show the interquartile ranges. Red circles: HIV positive and CMV negative individual; Red squares: HIV positive and CMV positive individual; blue circles: HIV negative and CMV negative individual; blue squares: HIV negative and CMV positive individual Eec ff t of infection with HIV and/or CMV on lymphocyte of a HIV-naïve control group [3]. Here we demonstrate subsets, T‑cell activation and T‑cell subpopulations that CMV coinfection may be a major but not exclusive In our four cohorts matched for sex and age, we found cause of residual T-cell activation in treated HIV-infected that treated HIV monoinfection and isolated CMV infec- individuals. Other factors that are proposed to contrib- tion are associated with similar levels of activation of ute to T-cell activation in this setting are age, microbial CD8 T cells with a cumulative effect in PLWH with long translocation, and residual replication of HIV in latently term ART and CMV coinfection resulting in high num- infected cells [22]. bers of activated CD8 T cells. Wittkop and colleagues Both monoinfection with CMV and effectively treated similarly demonstrated that CMV infection is associated HIV-monoinfection were associated with expansion of with activation of CD8 T cells in treated HIV-infected CD8 T cells to comparable levels, resulting in a cumula- individuals but they were not able to show the differen - tive effect in people coinfected with HIV/CMV. Greater tial effect of HIV and CMV infection due to the absence CD8 T-cell inflation in combination with HIV-induced Mueller et al. AIDS Res Ther (2021) 18:37 Page 6 of 9 Fig. 3 Serum concentrations of inflammation markers. A Serum levels of soluble CD 163 (sCD163) and B C‑reactive protein (CRP) in CMV seropositive and seronegative HIV‑infected patients on long term ART and HIV ‑naïve control group. Black horizontal lines correspond to the median and errors bars show the interquartile ranges. Red cricles: HIV positive and CMV negative individual; red squares: HIV positive and CMV positive individual; blue circles: HIV negative and CMV negative individual; blue squares: HIV negative and CMV positive individual reduction of CD4 T-cell counts led to a CD4/CD8 ratio of late effector and terminally differentiated CD8 T cells below 1 in CMV coinfected patients. Patients with strongly decreased after initiation of ART but remained treated HIV-monoinfection or isolated CMV-infection significantly higher compared to HIV-negative individu - displayed similar reduction of CD4/CD8 ratios com- als after up to 144  weeks of treatment [17, 25]. Because pared to CMV−/HIV-naïve individuals. Freeman and the studies were controlled for age and sex, but not for colleagues showed similar results concerning the effect of CMV serostatus, it may be assumed that the persistent CMV coinfection on CD8 expansion and CD4/CD8 ratio alterations of the distribution of late effector and termi - in treated HIV-positive individuals [14]. Their incapa - nally differentiated CD8 T cells is probably due to the bility to attribute CD8 T-cell expansion to treated HIV- more pronounced effect of CMV infection on late effec - monoinfection and to demonstrate an effect of CMV tor CD8 T cells in individuals with HIV and the higher infection on CD4/CD8 ratio in HIV-naïve patients may prevalence of CMV infection in HIV-cohorts compared be probably due to missed matching for CMV status, sex to the general population. Thus, the persistence of ele - and age of HIV-negative controls [14, 23]. Indeed, previ- vated levels of late effector and terminally differentiated ous studies demonstrated a clear effect of CMV infection T cells in PLWH under effective ART is probably not a on the frequency of CD8 T cells and on the CD4/CD8 residual effect of HIV-infection but mainly attributable to ratio in HIV-negative, especially elderly individuals [23, CMV coinfection. 24]. Our results are in line with previous data showing an The effect of infection with HIV and/or CMV on late association between CMV infection and high propor- effector CD8 T cells and terminally differentiated CD8 T tion of CD28−CD8+ T cells expressing CD57 in HIV- cells showed similar patterns. CMV infection was asso- naïve individuals [23]. In concordance to the results of ciated with high numbers of late effector and terminally the study of Lee and colleagues restricted to patients differentiated CD8 T cells in HIV-naïve and PLWH on with confirmed latent CMV infection, we show that ART, showing a stronger effect of CMV infection on the treated HIV infection compared to CMV-monoinfection levels of late effector T cells in treated HIV-positive than is associated with lower proportion of CD28−CD8+ T in HIV-naïve individuals. Whereas the absolute num- cells expressing CD57 [15]. Higher absolute numbers of bers of late effector and terminally differentiated T cells CD28−CD57+CD8+ T cells were due to an expansion in CMV-monoinfected patients were clearly raised, the of CD28−CD8+ populations in HIV−/CMV-coinfected effect of treated HIV-monoinfection compared to CMV/ individuals, suggesting that HIV preferentially expands HIV naïve study participants showed no statistically sig- CD28−CD57−CD8+ T cells and impedes the terminal nificant effect. Previous studies showed that proportions differentiation of CD28−CD8+ T cells. This effect of M ueller et al. AIDS Res Ther (2021) 18:37 Page 7 of 9 HIV on the differentiation process of CD8 T cells may coinfected compared to HIV monoinfected subjects explain our findings that frequencies of CD28−CD8+ T matched for age, CD4 nadir, HIV infection duration, and cells expressing CD57 were comparable in both cohorts viral hepatitis status [37]. Interestingly, sCD163 con- of HIV-infected individuals regardless of CMV serosta- centrations of patients with HIV monoinfection were tus, suggesting that HIV infection may have a modula- comparable with those who were not infected with HIV, tory effect on the T-cell response to CMV infection. suggesting a driving role of chronic CMV infection in These alterations of the T-cell compartment may have monocyte/macrophage activation in treated individuals consequences in the clinical outcome. In the HIV‐nega- with HIV. Levels of sCD163 were positively correlated tive population, a low CD4/CD8 ratio has been asso- with duration of HIV infection which could explain the ciated with near‐term mortality in the elderly [26]. In absence of an effect of CMV on sCD163 levels in our ART-treated HIV-infected individuals, expansion of study as we did not match for this variable. But in our CD8 T cells and inversion of CD4/CD8 ratio has been study, we could not confirm the association of duration linked to an increased morbidity and mortality, even of HIV infection and sCD163. in the setting of CD4 T-cell counts within the refer- A limitation of our study is the relatively small sample ence range [27, 28]. Associations of higher frequencies size. Differences which did not reach statistical signifi - of terminally differentiated (CD28−CD57+) and acti - cance in our study may become statistically significant vated (CD38+HLA−DR+) CD8+ T cells with subclini- in a larger sample set. Although we employed a prospec- cal carotid artery disease have been described in PLWH tive study design, some data had to be extracted from [29]. These markers were also used to generate a score of patients’ records leading to an incomplete data set in immune activation and senescence which showed a sta- some of the items. tistically significant association with the development of non-AIDS related morbidities in treated patients younger Conclusions than 60 years [30]. We could show that latent CMV infection is probably the It has been proposed that the HIV-induced impediment major contributor to persistent alterations in the T-cell of terminal differentiation of CD28−CD8+ T cells may compartment linked to adverse clinical outcomes in lead to a functional immune defect as CD57+CD8+ T treated HIV infection and that HIV infection may mod- cells are believed to be highly effective at killing infected ulate T-cell response against CMV infection. Therefore, cells and a high percentage of CD57+CD8+ T cells has future studies investigating immune senescence should been shown to be associated with lower HIV RNA level always control for CMV serostatus. set-points [15, 31, 32]. Furthermore, Lee and colleagues In both HIV and CMV infection perpetual antigen could show that low proportions of CD28−CD8+ T cells presentation is the driving force of these changes in expressing CD57+ predicts increased all-cause mortality the T-cell compartment. In the setting of HIV infec- in PLWH under ART [16]. tion it is now widely accepted that suppressive therapy of HIV replication improves parameters of immune Eec ff t of infection with HIV and/or CMV on markers activation, immune senescence and inflammation and of inflammation and monocyte/macrophages activation reduces the incidence of non-AIDS-associated mor- In the current study, concentrations of CRP and sCD163 bidities [38, 39]. in PLWH were in the magnitude of those of HIV-neg- In the setting of CMV infection, it has been shown that ative individuals without effect of CMV. Previous stud - valganciclovir reduces CMV replication and CD8 T-cell ies agree that CRP is elevated and persists in chronically activation in treated HIV-infected individuals but trials HIV-infected patients without effect of ART even after evaluating the effect of anti-CMV therapy on markers several years of treatment [8, 33, 34]. Valid data on the of immune senescence and the incidence on age-related effect of CMV infection on CRP levels are scarce. The morbidity are lacking [12]. Because novel, well tolerated available evidence shows an effect of CMV infection on anti-CMV therapies are now available, CMV infection CRP levels in HIV-negative patients and HIV-positive may be an attractive target for therapeutic interventions individuals with and without ART [35, 36]. Concern- in individuals with HIV on effective ART [40]. ing sCD163, previously published results of compara- ble cohorts showed higher concentrations of sCD163 in PLWH under long term ART and undetectable HIV Abbreviations ART : Antiretroviral therapy; CMV: Cytomegalovirus; CRP: C‑reactive protein; RNA levels compared to age matched HIV-seronegative IQR: Interquartile range; PLWH: People living with HIV; sCD14: Soluble CD14; controls, but none of them was controlled for CMV sCD163: Soluble CD163. serostatus [5, 6, 11]. Vita and colleagues found sig- nificantly higher sCD163 plasma levels in HIV/CMV Mueller et al. AIDS Res Ther (2021) 18:37 Page 8 of 9 immune response, and microbial translocation on chronic immune Supplementary Information activation in successfully treated HIV type 1‑infected patients: the ANRS The online version contains supplementary material available at https:// doi. CO3 aquitaine cohort. J Infect Dis. 2013;207:622–7. org/ 10. 1186/ s12981‑ 021‑ 00361‑z. 4. Di Benedetto S, Derhovanessian E, Steinhagen‑ Thiessen E, Goldeck D, Müller L, Pawelec G. Impact of age, sex and CMV‑infection on peripheral T cell phenotypes: results from the Berlin BASE‑II study. Biogerontology. Additional file 1: Table S1. Table with antibodies used for Lymphocyte 2015;16:631–43. and T‑ cell subpopulations phenotyping by flow cytometry. 5. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, Additional file 2: Figure S1. Gating strategy for T ‑ cell subsets. a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV ‑infected patients. J Infect Dis. Additional file 3: Figure S2. Gating strategy for lymphocyte subsets. 2011;204:1227–36. 6. McKibben RA, Margolick JB, Grinspoon S, Li X, Palella FJ, Kingsley LA, et al. Elevated levels of monocyte activation markers are associated with Acknowledgements subclinical atherosclerosis in men with and those without HIV infection. J Not applicable. Infect Dis. 2015;211:1219–28. 7. Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, et al. Plasma Authors’ contributions levels of soluble CD14 independently predict mortality in HIV infection. J US and MCM contributed to the conception and design of the work, to the Infect Dis. 2011;203:780–90. acquisition, analysis, and interpretation of data for the work and drafted and 8. 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Immune resilience in The study was approved by the institutional ethics review board of the HIV‑infected individuals seronegative for cytomegalovirus. AIDS. medical center of the University of Freiburg (No.: 317/15, Date: 31 July 2015). 2014;28:2045. All HIV‑infected persons were recruited at the HIV Centre of Freiburg and 14. Freeman ML, Mudd JC, Shive CL, Younes SA, Panigrahi S, Sieg SF, et al. provided written informed consent. Blood donors provided informed consent CD8 T‑ cell expansion and inflammation linked to CMV coinfection in ART ‑ for the scientific use of surplus portions of their blood donation. treated HIV infection. Clin Infect Dis. 2016;62:392–6. 15. Lee SA, Sinclair E, Hatano H, Hsue PY, Epling L, Hecht FM, et al. Impact Consent for publication of HIV on CD8+ T cell CD57 expression is distinct from that of CMV and Not applicable. aging. PLoS ONE. 2014;9:e89444. 16. Lee SA, Sinclair E, Jain V, Huang Y, Epling L, Van Natta M, et al. 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Lieberman J, Trimble L, Friedman R, Lisziewicz J, Lori F, Shankar P, et al. lished maps and institutional affiliations. Expansion of CD57 and CD62L−CD45RA+ CD8 T lymphocytes cor‑ relates with reduced viral plasma RNA after primary HIV infection. AIDS. 1999;13:891–9. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AIDS Research and Therapy Springer Journals

Assessing the differential impact of chronic CMV and treated HIV infection on CD8+ T-cell differentiation in a matched cohort study: is CMV the key?

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Abstract

Background: Cytomegalovirus (CMV ) infection is one of the main driving forces of T‑ cell senescence in the gen‑ eral population, whereas its differential impact in people living with HIV (PLWH) is less well characterized. The study explores the effect of latent CMV infection on T ‑ cell subsets, monocyte/macrophages activation markers, and CRP in PLWH on long‑term ART. Methods: Cross‑sectional cohort study including PLWH on long‑term suppressive ART. Individuals of 4 groups (HIV+CMV−, HIV+CMV+, HIV−CMV+, and HIV−CMV−) were matched 1:1:1:1 for age and sex. Immunophenotyping of lymphocyte and T‑ cell subsets by multicolor flow cytometry was performed in fresh blood samples collected from patients and healthy donors. Results: Both, latent CMV and treated HIV infection were associated with an expansion of CD8 T cells, a reduced CD4/CD8 ratio, and with CD8 T‑ cell activation with a cumulative effect in CMV/HIV ‑ coinfected individuals. CMV was associated with elevated numbers of late effector and terminally differentiated CD8 T ‑ cells. Compared to CMV mono‑ infection, CMV/HIV coinfection showed to be associated with lower proportion of CD28−CD8+ T cells expressing CD57 suggesting that HIV preferentially expands CD28−CD57−CD8+ T cells and impedes terminal differentiation of CD28−CD8+ T cells. We could not show any association between HIV or CMV infection status and concentration of CRP and CD163. Conclusions: CMV infection is associated with phenotypic signs of T‑ cell senescence, promoting exacerbation and persistence of alterations of the T‑ cell compartment in PLWH on effective ART, which are associated with adverse clini‑ cal outcomes and may be an attractive target for therapeutic interventions. Keywords: HIV, CMV, T‑ cell senescence, CD163, CRP, Inflammation Background Antiretroviral therapy (ART) led to a remarkable improvement in long-term life-expectancy of people liv- ing with HIV (PLWH) [1]. Despite treatment-mediated *Correspondence: matthias.mueller@uniklinik‑freiburg.de continuous suppression of HIV replication and consecu- Division of Infectious Diseases, Department of Medicine II, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, tive restoration of CD4 cell count, PLWH retain a higher Hugstetter Straße 55, 79106 Freiburg, Germany risk for death and aging-related disorders including Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mueller et al. AIDS Res Ther (2021) 18:37 Page 2 of 9 cardiovascular, renal, liver, neurologic, and bone disease prevalence in the general population increases with age [2]. Because HIV induces immunologic dysfunctions and is 55% among blood donors in Germany, whereas the showing similarities to those observed in elderly popula- CMV prevalence in HIV cohorts generally is about 90% tions, it has been hypothesized that HIV-induced accel- independent of age [20, 21]. erated aging of the immune system (immune senescence) To evaluate the differential effect of CMV and HIV could mediate these risks. infection on markers of immune dysfunction, we per- T-cell senescence, whether driven by aging and/or by formed a cohort study matching for sex and age CMV- chronic antigenic stimulation from pathogens such as negative and -positive individuals with and without HIV HIV or cytomegalovirus (CMV), is typically character- infection. ized by T-cell activation, inversion of the CD4/CD8 ratio due to low CD4 T-cell counts and accumulation of ter- Methods minally differentiated CD8 T cells with shortened telom - Ethics consideration eres, a decrease in the costimulatory molecule CD28, and The study was approved by the institutional ethics review increased expression of CD57, a marker of proliferative board of the medical center of the University of Freiburg history and poor proliferative capacity [3, 4]. (No.: 317/15, Date: 31 July 2015). All PLWH  were Markers of inflammation like c-reactive protein (CRP) recruited at the HIV Centre Freiburg and provided writ- and of monocyte/macrophage activation, like soluble ten informed consent. Blood donors provided informed CD14 (sCD14) and soluble CD163 (sCD163), have been consent for the scientific use of surplus portions of their shown to be elevated in HIV infection and to be asso- blood donation. ciated with the risk for non-AIDS-defining morbidity, especially with cardiovascular disease [5–11]. Study design/setting In PLWH, ART improves many of these HIV-induced This cross-sectional cohort study was carried out at the immunologic alterations, but the effect is incomplete, HIV Centre Freiburg, Germany, caring for about 800 and markers of immune activation, inflammation and PLWH. Patients were enrolled between November 26, T-cell differentiation remain altered. The mechanism 2015 and November 23, 2016. Because CMV seronega- inducing residual immune dysfunction is complex and tive PLWH are rare, patient records of PLWH attending multifactorial in origin. Chronic coinfection with CMV the HIV Centre Freiburg were screened for CMV seron- has been identified to strongly contribute to persistent egative patients. Blood samples were taken at enrollment immune activation, to be associated with lower CD4/ of patients and CMV serostatus was reassessed using a CD8 T-cell ratios, with reduced expression of CD28 and CMV immunoglobulin G (IgG) assay (Abbott Architect increased expression of CD57 in PLWH people with HIV CMV IgG CLIA, Abbott Diagnostics, Wiesbaden, Ger- on long term ART [3, 12–14]. many). HIV-infected CMV-seronegative patients were Differences in alterations of T-cell compartments then matched 1:1:1:1 for sex and age with HIV-infected, between HIV infection on one side and CMV monoin- CMV-seropositive patients and with HIV-uninfected, fection and aging on the other side may exist. In a study CMV-seropositive and CMV-seronegative blood donors of Lee and colleagues, CMV infection and aging were from the Blood Donation Center Freiburg. associated with high proportions CD28−CD8+ T-cells HIV-infected patients were eligible when they were expressing CD57, whereas PLWH showed an enrich- on ART with ≥ 12  months of HIV RNA < 20  cp/ml. ment of less well-differentiated transitional CD8+ T cells Exclusion criteria for HIV-infected patients were active and abnormally low proportions of CD28−CD8+ T cells Hepatitis B or Hepatitis C, untreated sexual transmitted expressing CD57. In a consecutive study, the authors disease (syphilis, gonorrhea, and Chlamydia trachomatis could show that low proportions of CD28−CD8+ T cells infection), previous or current CMV-related organ dis- expressing CD57 strongly predicted increased all-cause eases, organ transplantation, as well as cancer or treat- mortality in PLWH under ART [15, 16]. These studies ment of cancer, autoimmune disease with or without use however did not assess the effect of CMV coinfection on of immunosuppressive or immunomodulant drugs in the the magnitude of CD57 expression of CD28−CD8+ T previous 5 years. cells and on clinical outcome. Equally, many other studies assessing the HIV-induced Study diagnostic procedures effects on immune senescence did not control for CMV Lymphocyte and T‑cell subpopulations phenotyping coinfection and/or did not employ HIV-negative indi- Phenotyping of T-, B- and NK cells within the lympho- viduals, making it impossible to discriminate the effects cyte population as well as T-cell subpopulations was per- of CMV and HIV on the immune dysfunction perceived formed by a whole blood staining lyse-no wash protocol in PLWH on long term ART [3, 12–14, 17–19]. CMV (Optilyse B, Beckman-Coulter) using six colour flow M ueller et al. AIDS Res Ther (2021) 18:37 Page 3 of 9 cytometry with fluorochrome-conjugated antibodies as Results listed in Additional file 1: Table S1. A total of 92 patients were included in the study, form- Antibody labelled cells were analyzed by flow cytom - ing 23 sets with each 4 matched individuals. Median age etry (Navios; Beckman Coulter). Absolute cell counts was 49.4  years [interquartile range (IQR), 44.3–54.3] were calculated using a two platform method with leu- and 30.4% of participants were women without differ - cocyte and lymphocyte counts determined by a hemo- ences between the 4 groups (Table  1). Median time of cytometer. Flow cytometric data analysis was performed HIV RNA below limit of detection was 64 months (IQR, with the help of Kaluza Software 1.5a (Beckman Coulter). 20–96) in HIV+CMV+ and 62 months (IQR, 15–108) in Representative gating strategies for analysed populations HIV+CMV− patients. are shown in Additional file  2: Figure S1 and Additional file 3: Figure S2. Lymphocyte and T‑cell subpopulations phenotyping As expected, lymphocyte subpopulation analysis revealed lower amounts of CD4+ T cells in HIV infected indi- sCD163 and CRP analysis HIV+CMV+ HIV− viduals (median = 469.5/µl versus me dian sCD163 concentrations in cryopreserved plasma samples CMV+ HIV+CMV− = 825.0/µl; p = 0.0049 and median = 564/ were quantified by using a commercially available ELISA HIV−CMV− µl versus median = 758.0/µl; p = 0.0115) but kit (Quantikine, R&D Systems, Minneapolis, MN, United there was no significant difference between the CMV+ States of America). All samples were tested in duplicate. and CMV− groups both in PLWH and healthy controls hsCRP concentrations in cryopreserved plasma sam- (Fig.  1A). The further analysis revealed higher absolute ples were quantified by using the standard immunotur - numbers of CD8+ T cells in CMV+ patients both in bidometric assay on the COBAS INTEGRA system HIV+CMV+ the HIV− and HIV+ groups (median = 700/ (Roche COBAS INTEGRA, Roche Diagnostics, Basel HIV+CMV− µl versus me dian = 491.5/µl, p = 0.0102 Switzerland). HIV−CMV+ HIV− and median = 482.0/µl versus median CMV− = 306/µl, p = 0.0002; Fig.  1B) and a significantly Statistical analysis lower CD4/CD8 ratio in CMV+ subjects both in the HIV+CMV+ A Kruskal–Wallis test was conducted to determine if HIV− and HIV+ groups (me dian = 0.74 ver- HIV+CMV− HIV− levels of CRP and sCD163 were statistically different sus median = 1.32, p = 0.0006 and me dian CMV+ HIV−CMV− between the four cohorts. Spearman’s rank correlation = 1.67 versus median = 2.93; p = 0.0023, coefficient was calculated to determine associations Fig. 1C). between variables. For pairwise statistical analysis of flow cytometric two sided Wilcoxon matched-pairs signed T‑cell subpopulations phenotyping rank test (analyzed data showed a non-Gaussian dis- For analysis of T-cell activation markers, HLA-DR was tribution) was performed for cell counts of individual counterstained and analyzed on CD3+, CD4+ and cell populations. Normality testing was done using the CD8+ T cells. This showed higher absolute numbers D’Agostino & Pearson normality test. Statistical results of CD8+HLA−DR+ T cells in CMV+ patients both in HIV+CMV+ were calculated with the of Graphpad Prism Software the HIV− and HIV+ groups (median = 118/ HIV+CMV− version 8 (Graphpad Software, San Diego, USA). µl versus median = 71/µl, p = 0.0176 and Table 1 Baseline characteristics of participating patients matched for sex and age recruited from a HIV cohort between November 2015 and November 2016 Total HIV+ HIV− CMV+ CMV− CMV+ CMV− n 92 23 23 23 23 Female, n (%) 28 (30.4) 7 (30.4) 7 (30.4) 7 (30.4) 7 (30.4) Age (y), median (IQR) 49.4 (44.3–54.3) 50.1 (44.3–54.3) 48.6 (44.3–54.0) 49.4 (44.1–55.4) 49.5 (45.2–55.0) Time since HIV infection (y), median (IQR) 14.5 (6.6–21.0) 12.5 (6.6–19.7) 17.1 (6.5–23.1) NA NA CD4 nadir (cells/µl), median (IQR) 190.5 (95.0–255.0) 197.0 (95.0–257.0) 173.5 (95.0–223.0) NA NA VL < LoD (months), median (IQR) 63.0 (20.0–99.0) 64.0 (20.0–96.0) 62.0 (15.0–108.0) NA NA CD4, (cells/µl), median (IQR) NA 469.5 (364.5–635.3) 564.0 (380.8–727.3) 825.0 (584.8–1054.0) 758.0 (593.0–1045.0) VL viral load, LoD limit of detection, y year, ART antiretroviral therapy, CMV cytomegalovirus, NA not applicable, IQR interquartile range Mueller et al. AIDS Res Ther (2021) 18:37 Page 4 of 9 Fig. 1 Lymphocyte subsets and activated T cells. A Absolute counts of CD4+ T cells/µl. B absolute counts of CD8+ T cells/µl. C CD4/CD8 ratio. Black horizontal lines correspond to the median and errors bars show the interquartile ranges. Red circles: HIV positive and CMV negative individual; red squares: HIV positive and CMV positive individual; blue circles: HIV negative and CMV negative individual; blue squares: HIV negative and CMV positive individual HIV−CMV+ HIV−CMV− median = 51/µl versus me dian = 37/ 437.0–634.0  ng/ml) and HIV−CMV−: 609  ng/ml µl, p = 0.0072; Fig. 2A). (IQR, 472.0–695.0  ng/ml), p = 0.9208] (Fig .  3). Corre- Naïve CD4+CD45RA+ T cells were lower in absolute lation analysis showed that sCD163 levels were posi- numbers in HIV+CMV+ patients when compared to tively correlated with age in the group of CMV+HIV+ HIV+CMV+ CMV+ healthy controls (median = 151/µl ver- (r = 0.49, p = 0.020) and in CMV+HIV− with border- HIV−CMV+ sus median = 339/µl, p = 0.0083) (Fig.  2B). The line statistical significance (r = 0.63, p = 0.062) but expanded CD8+ T-cell subset of CMV+ subjects was not in CMV− subgroups (CMV−HIV−: r = − 0.146, enriched for CD8+CD27−CD28− early and late effector p = 0.529; CMV−HIV+: r = 0.257, p = 0.274). We could HIV+CMV+ cells in HIV+ and HIV− groups (median = 269/ neither detect an association between sCD163 levels HIV+CMV− µl versus median = 36.5/µl, p < 0.0001 and and duration of HIV infection (CMV+HIV+: r = 0.311, HIV−CMV+ HIV−CMV− median = 134/µl versus median = 14/ p = 0.159; CMV−HIV+: r = 0.298, p = 0.202) nor µl; p < 0.0001) (Fig.  2C, D) and CD8+CD57+ termi- with CD4 Nadir (CMV+HIV+: r = − 0.181, p = 0.593; HIV+CMV+ nally differentiated CD8 T cells (median = 206/ CMV−HIV+: r = 0.128, p = 0.709) or current CD4 cell HIV+CMV− µl versus me dian = 77.5/µl; p = 0.0011 and count (CMV+HIV+: r = − 0.018, p = 0.9377; CMV− HIV−CMV+ HIV−CMV− median = 155/µl versus median = 49/ HIV+: r = 0.104, p = 0.6633). µl, p < 0.0001) (Fig.  2E). Within the CD8+CD28− In the 17 quadruples with available CRP concentra- T-cell subset the increase of CD57+ cells was even tion measurement of all four individuals the median HIV+CMV+ more significant (median = 200/µl versus CRP concentration was 1.2  mg/l (IQR, 0.7–3.0  ng/ HIV+CMV− HIV− median = 65.5/µl; p = 0.0003 and me dian ml), without differences between the four sub - CMV+ HIV−CMV− = 135/µl versus median = 29/µl, groups [HIV+CMV+: 1.6  mg/l (IQR, 1.0–3.5  mg/l), p < 0.0001) (Fig. 2F). HIV+CMV−: 1.2  mg/l (IQR, 0.7–2.25  mg/l), HIV− CMV+: 1.2 mg/l (IQR, 0.8–2.5 mg/l) and HIV−CMV−: 1.1 mg/l (IQR, 0.7–3.0 mg/l), p = 0.684] (Fig . 3). Markers of inflammation and monocyte activation In the 17 quadruples with available sCD163 con- centration measurement of all four patients the Discussion median sCD163 concentration was 555  ng/ml (IQR, To our knowledge, this is the first study showing the 408.0–733.5  ng/ml), without differences between differential impact of CMV infection and treated HIV the four subgroups [HIV+CMV+: 628  ng/ml (IQR, infection on T-cell subpopulations. 360.0–822.0  ng/ml), HIV+CMV−: 540  ng/ml (IQR, 396.0–725.0  ng/ml), HIV−CMV+: 520  ng/ml (IQR, M ueller et al. AIDS Res Ther (2021) 18:37 Page 5 of 9 Fig. 2 CD4+ and CD8+ T‑ cell subpopulations. A Absolute counts of CD8+ HLA‑DR+ T cells/µl. B Absolute counts of CD4+CD45RA+ naïve T cells/ µl. C absolute counts of CD8+CD28+ CD27− early effector T cells/µl. D Absolute counts CD8+CD28−CD27− late effector T cells/µl. E Absolute counts CD8+CD57+ terminally differentiated T cells/µl. F Absolute counts CD8+CD28−CD57+ terminally differentiated T cells/µl. Black horizontal lines correspond to the median and errors bars show the interquartile ranges. Red circles: HIV positive and CMV negative individual; Red squares: HIV positive and CMV positive individual; blue circles: HIV negative and CMV negative individual; blue squares: HIV negative and CMV positive individual Eec ff t of infection with HIV and/or CMV on lymphocyte of a HIV-naïve control group [3]. Here we demonstrate subsets, T‑cell activation and T‑cell subpopulations that CMV coinfection may be a major but not exclusive In our four cohorts matched for sex and age, we found cause of residual T-cell activation in treated HIV-infected that treated HIV monoinfection and isolated CMV infec- individuals. Other factors that are proposed to contrib- tion are associated with similar levels of activation of ute to T-cell activation in this setting are age, microbial CD8 T cells with a cumulative effect in PLWH with long translocation, and residual replication of HIV in latently term ART and CMV coinfection resulting in high num- infected cells [22]. bers of activated CD8 T cells. Wittkop and colleagues Both monoinfection with CMV and effectively treated similarly demonstrated that CMV infection is associated HIV-monoinfection were associated with expansion of with activation of CD8 T cells in treated HIV-infected CD8 T cells to comparable levels, resulting in a cumula- individuals but they were not able to show the differen - tive effect in people coinfected with HIV/CMV. Greater tial effect of HIV and CMV infection due to the absence CD8 T-cell inflation in combination with HIV-induced Mueller et al. AIDS Res Ther (2021) 18:37 Page 6 of 9 Fig. 3 Serum concentrations of inflammation markers. A Serum levels of soluble CD 163 (sCD163) and B C‑reactive protein (CRP) in CMV seropositive and seronegative HIV‑infected patients on long term ART and HIV ‑naïve control group. Black horizontal lines correspond to the median and errors bars show the interquartile ranges. Red cricles: HIV positive and CMV negative individual; red squares: HIV positive and CMV positive individual; blue circles: HIV negative and CMV negative individual; blue squares: HIV negative and CMV positive individual reduction of CD4 T-cell counts led to a CD4/CD8 ratio of late effector and terminally differentiated CD8 T cells below 1 in CMV coinfected patients. Patients with strongly decreased after initiation of ART but remained treated HIV-monoinfection or isolated CMV-infection significantly higher compared to HIV-negative individu - displayed similar reduction of CD4/CD8 ratios com- als after up to 144  weeks of treatment [17, 25]. Because pared to CMV−/HIV-naïve individuals. Freeman and the studies were controlled for age and sex, but not for colleagues showed similar results concerning the effect of CMV serostatus, it may be assumed that the persistent CMV coinfection on CD8 expansion and CD4/CD8 ratio alterations of the distribution of late effector and termi - in treated HIV-positive individuals [14]. Their incapa - nally differentiated CD8 T cells is probably due to the bility to attribute CD8 T-cell expansion to treated HIV- more pronounced effect of CMV infection on late effec - monoinfection and to demonstrate an effect of CMV tor CD8 T cells in individuals with HIV and the higher infection on CD4/CD8 ratio in HIV-naïve patients may prevalence of CMV infection in HIV-cohorts compared be probably due to missed matching for CMV status, sex to the general population. Thus, the persistence of ele - and age of HIV-negative controls [14, 23]. Indeed, previ- vated levels of late effector and terminally differentiated ous studies demonstrated a clear effect of CMV infection T cells in PLWH under effective ART is probably not a on the frequency of CD8 T cells and on the CD4/CD8 residual effect of HIV-infection but mainly attributable to ratio in HIV-negative, especially elderly individuals [23, CMV coinfection. 24]. Our results are in line with previous data showing an The effect of infection with HIV and/or CMV on late association between CMV infection and high propor- effector CD8 T cells and terminally differentiated CD8 T tion of CD28−CD8+ T cells expressing CD57 in HIV- cells showed similar patterns. CMV infection was asso- naïve individuals [23]. In concordance to the results of ciated with high numbers of late effector and terminally the study of Lee and colleagues restricted to patients differentiated CD8 T cells in HIV-naïve and PLWH on with confirmed latent CMV infection, we show that ART, showing a stronger effect of CMV infection on the treated HIV infection compared to CMV-monoinfection levels of late effector T cells in treated HIV-positive than is associated with lower proportion of CD28−CD8+ T in HIV-naïve individuals. Whereas the absolute num- cells expressing CD57 [15]. Higher absolute numbers of bers of late effector and terminally differentiated T cells CD28−CD57+CD8+ T cells were due to an expansion in CMV-monoinfected patients were clearly raised, the of CD28−CD8+ populations in HIV−/CMV-coinfected effect of treated HIV-monoinfection compared to CMV/ individuals, suggesting that HIV preferentially expands HIV naïve study participants showed no statistically sig- CD28−CD57−CD8+ T cells and impedes the terminal nificant effect. Previous studies showed that proportions differentiation of CD28−CD8+ T cells. This effect of M ueller et al. AIDS Res Ther (2021) 18:37 Page 7 of 9 HIV on the differentiation process of CD8 T cells may coinfected compared to HIV monoinfected subjects explain our findings that frequencies of CD28−CD8+ T matched for age, CD4 nadir, HIV infection duration, and cells expressing CD57 were comparable in both cohorts viral hepatitis status [37]. Interestingly, sCD163 con- of HIV-infected individuals regardless of CMV serosta- centrations of patients with HIV monoinfection were tus, suggesting that HIV infection may have a modula- comparable with those who were not infected with HIV, tory effect on the T-cell response to CMV infection. suggesting a driving role of chronic CMV infection in These alterations of the T-cell compartment may have monocyte/macrophage activation in treated individuals consequences in the clinical outcome. In the HIV‐nega- with HIV. Levels of sCD163 were positively correlated tive population, a low CD4/CD8 ratio has been asso- with duration of HIV infection which could explain the ciated with near‐term mortality in the elderly [26]. In absence of an effect of CMV on sCD163 levels in our ART-treated HIV-infected individuals, expansion of study as we did not match for this variable. But in our CD8 T cells and inversion of CD4/CD8 ratio has been study, we could not confirm the association of duration linked to an increased morbidity and mortality, even of HIV infection and sCD163. in the setting of CD4 T-cell counts within the refer- A limitation of our study is the relatively small sample ence range [27, 28]. Associations of higher frequencies size. Differences which did not reach statistical signifi - of terminally differentiated (CD28−CD57+) and acti - cance in our study may become statistically significant vated (CD38+HLA−DR+) CD8+ T cells with subclini- in a larger sample set. Although we employed a prospec- cal carotid artery disease have been described in PLWH tive study design, some data had to be extracted from [29]. These markers were also used to generate a score of patients’ records leading to an incomplete data set in immune activation and senescence which showed a sta- some of the items. tistically significant association with the development of non-AIDS related morbidities in treated patients younger Conclusions than 60 years [30]. We could show that latent CMV infection is probably the It has been proposed that the HIV-induced impediment major contributor to persistent alterations in the T-cell of terminal differentiation of CD28−CD8+ T cells may compartment linked to adverse clinical outcomes in lead to a functional immune defect as CD57+CD8+ T treated HIV infection and that HIV infection may mod- cells are believed to be highly effective at killing infected ulate T-cell response against CMV infection. Therefore, cells and a high percentage of CD57+CD8+ T cells has future studies investigating immune senescence should been shown to be associated with lower HIV RNA level always control for CMV serostatus. set-points [15, 31, 32]. Furthermore, Lee and colleagues In both HIV and CMV infection perpetual antigen could show that low proportions of CD28−CD8+ T cells presentation is the driving force of these changes in expressing CD57+ predicts increased all-cause mortality the T-cell compartment. In the setting of HIV infec- in PLWH under ART [16]. tion it is now widely accepted that suppressive therapy of HIV replication improves parameters of immune Eec ff t of infection with HIV and/or CMV on markers activation, immune senescence and inflammation and of inflammation and monocyte/macrophages activation reduces the incidence of non-AIDS-associated mor- In the current study, concentrations of CRP and sCD163 bidities [38, 39]. in PLWH were in the magnitude of those of HIV-neg- In the setting of CMV infection, it has been shown that ative individuals without effect of CMV. Previous stud - valganciclovir reduces CMV replication and CD8 T-cell ies agree that CRP is elevated and persists in chronically activation in treated HIV-infected individuals but trials HIV-infected patients without effect of ART even after evaluating the effect of anti-CMV therapy on markers several years of treatment [8, 33, 34]. Valid data on the of immune senescence and the incidence on age-related effect of CMV infection on CRP levels are scarce. The morbidity are lacking [12]. Because novel, well tolerated available evidence shows an effect of CMV infection on anti-CMV therapies are now available, CMV infection CRP levels in HIV-negative patients and HIV-positive may be an attractive target for therapeutic interventions individuals with and without ART [35, 36]. Concern- in individuals with HIV on effective ART [40]. ing sCD163, previously published results of compara- ble cohorts showed higher concentrations of sCD163 in PLWH under long term ART and undetectable HIV Abbreviations ART : Antiretroviral therapy; CMV: Cytomegalovirus; CRP: C‑reactive protein; RNA levels compared to age matched HIV-seronegative IQR: Interquartile range; PLWH: People living with HIV; sCD14: Soluble CD14; controls, but none of them was controlled for CMV sCD163: Soluble CD163. serostatus [5, 6, 11]. Vita and colleagues found sig- nificantly higher sCD163 plasma levels in HIV/CMV Mueller et al. AIDS Res Ther (2021) 18:37 Page 8 of 9 immune response, and microbial translocation on chronic immune Supplementary Information activation in successfully treated HIV type 1‑infected patients: the ANRS The online version contains supplementary material available at https:// doi. CO3 aquitaine cohort. J Infect Dis. 2013;207:622–7. org/ 10. 1186/ s12981‑ 021‑ 00361‑z. 4. Di Benedetto S, Derhovanessian E, Steinhagen‑ Thiessen E, Goldeck D, Müller L, Pawelec G. Impact of age, sex and CMV‑infection on peripheral T cell phenotypes: results from the Berlin BASE‑II study. Biogerontology. Additional file 1: Table S1. Table with antibodies used for Lymphocyte 2015;16:631–43. and T‑ cell subpopulations phenotyping by flow cytometry. 5. Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, Additional file 2: Figure S1. 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JAMA J Am Med Assoc. received no specific grant from any funding agency, or commercial or not ‑for ‑ 2012;308:379–86. profit organization. 11. Ananworanich J, Kerr SJ, Jaimulwong T, Vibol U, Hansudewechakul R, Kosalaraksa P, et al. Soluble CD163 and monocyte populations in Availability of data and materials response to antiretroviral therapy and in relationship with neuropsycho‑ All data generated or analyzed during this study are included in this published logical testing among HIV‑infected children. J Virus Erad. 2015;1:196–202. article and its Additional files. 12. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, et al. Valganciclovir reduces T cell activation in HIV‑infected individuals with Declarations incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203:1474–83. Ethics approval and consent to participate 13. Barrett L, Stapleton SN, Fudge NJ, Grant MD. 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Lieberman J, Trimble L, Friedman R, Lisziewicz J, Lori F, Shankar P, et al. lished maps and institutional affiliations. Expansion of CD57 and CD62L−CD45RA+ CD8 T lymphocytes cor‑ relates with reduced viral plasma RNA after primary HIV infection. AIDS. 1999;13:891–9. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

AIDS Research and Therapy – Springer Journals

Published: Jun 30, 2021

Keywords: HIV; CMV; T-cell senescence; CD163; CRP; Inflammation

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