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. 2016 Nov;186(2):227-238.
doi: 10.1111/cei.12837. Epub 2016 Aug 23.

Partial recovery of senescence and differentiation disturbances in CD8+ T cell effector-memory cells in HIV-1 infection after initiation of anti-retroviral treatment

J M Eberhard  1   2 , F Ahmad  3 , H S Hong  3   4 , N Bhatnagar  3   5 , P Keudel  3 , J Schulze Zur Wiesch  6   7 , R E Schmidt  3   7 , D Meyer-Olson  3
Affiliations

Partial recovery of senescence and differentiation disturbances in CD8+ T cell effector-memory cells in HIV-1 infection after initiation of anti-retroviral treatment

J M Eberhard et al. Clin Exp Immunol. 2016 Nov.

Abstract

Immune senescence as well as disturbed CD8+ T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of anti-retroviral treatment (ART). Peripheral blood mononuclear cells (PBMCs) from a cohort of HIV patients with different disease courses, including untreated viral controllers (n = 10), viral non-controllers (n = 16) and patients on ART (n = 20), were analysed and compared to uninfected controls (n = 25) by flow cytometry on bulk and HIV-specific major histocompatibility complex (MHC) class I tetramer+ CD8+ T cells for expression of the memory markers CCR7 and CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127. Furthermore, a subset of patients was analysed longitudinally before and after initiation of ART. Frequencies of CD57+ CD8+ T cells decreased after initiation of ART in central memory (Tcm) but not in effector memory T cell populations (TemRO and TemRA). The frequency of CD127+ CD8+ cells increased in Tcm and TemRO. We observed a reduction of CD127- T cells in Tcm, TemRO and partially in TemRA subsets after initiation of ART. Importantly, HIV-specific CD8+ TemRO cells predominantly displayed a CD127- CD57+ phenotype in untreated HIV-patients, whereas the CD127+ CD57- phenotype was under-represented in these patients. The frequency of the CD127+ CD57- CD8+ T cell subpopulation correlated strongly with absolute CD4+ counts in HIV-infected patients before and after initiation of ART. These findings can be interpreted as a phenotypical correlate of CD8+ memory T cell differentiation and the premature 'ageing' of the immune system, which was even observed in successfully virally suppressed HIV patients.

Keywords: AIDS; T cells; cytotoxic T cells; viral.

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Figures

Figure 1
Figure 1
Elevated senescence and reduced survival capacity in naive, central memory and effector memory CD8+ T cells in HIV infection. Cumulative data from cross‐sectional flow cytometry analyses of CD57 expression (a–d) (21 (left panel) or 9 (right panel)) healthy donors, 9 viral controllers, 12 viral non‐controllers and 10 treated patients). Each symbol represents CD57+ cell numbers in percent of the CD8+ T cell subpopulation (frequency) or per μl of blood (absolute numbers). Cumulative data from cross‐sectional flow cytometry analyses of CD127 expression (E–H) (9 healthy donors, 9 viral controllers, 12 viral non‐controllers and 10 treated patients). Each symbol represents CD127+ cell numbers in percent of the CD8+ T cell subpopulation (frequency) or per μl of blood (absolute numbers).
Figure 2
Figure 2
Elevated CD57 and reduced CD127 expression on HIV‐1‐specific CD8+ T cells. (a) Flow cytometry plot of HIV‐1 tetramer staining (EI8, Gag derived) (left). Flow cytometry plot overlay depicting tetramer positive cells in the CD8+ T cell population (centre). Flow cytometry plot depicting gating strategy for tetramer‐negative versus tetramer‐positive cells within the CD8+ TemRO population (right). (b) Histogram [depicting a human leucocyte antigen (HLA)‐B*08‐positive patient] and cumulative display of CD57 expression‐analysis and (c) CD127 expression analysis. Compared were tetramer‐positive and ‐negative CD8+ TemRO cells from nine untreated patients. Tetramers contained HLA B*08, B*57 and B*27 restricted Gag‐ and Nef‐ derived peptides (KF11, KK10, FL8 and EI8). Statistical significance comparing tetramer‐negative and ‐positive cells was determined via paired t‐test and defined as P < 0·05. (d) Cumulative display of combined CD127 and CD57 expression analysis on tetramer‐positive versus tetramer‐negative CD8+ TemRO cells from eight untreated HIV‐1 infected patients. Tetramers contained HLA B*08, B*57 and B*27 restricted Gag‐ and Nef‐derived peptides (KF11, KK10, Fl8 and EI8). (e) Pie charts depicting mean percentages of each CD127/CD57 subset for tetramer‐positive and ‐negative cells.
Figure 3
Figure 3
Elevated senescence is not reduced after 9 months of anti‐retroviral treatment (ART) within the early effector memory population. Cumulative data of longitudinal flow cytometry analyses of eight patients before and after at least 9 months of ART compared to healthy controls. Bar graphs depict mean numbers of CD57+ (white) and CD57– (grey) cells per μl of blood. Connecting lines indicate longitudinal analysis.
Figure 4
Figure 4
Restored survival capacity after 9 months of anti‐retroviral treatment (ART) within the early effector memory population. Cumulative data of longitudinal flow cytometry analyses of eight patients before and after at least 9 months of ART compared to healthy controls. Bar graphs depict mean numbers of CD127+ (white) and CD127– (grey) cells per μl of blood. Connecting lines indicate longitudinal analysis.
Figure 5
Figure 5
Skewed association between CD57 and CD127 expression within early effector memory CD8+ T cells in HIV infection reveals expansion of CD127– subpopulations in HIV that are reduced under anti‐retroviral treatment (ART). (a) Representative flow cytometry plots depicting the subset definition within the CD8+ TemRO population according to their CD127 and CD57 expression in healthy controls and HIV patients before and upon the start of ART. (b) Longitudinal analysis of differentially CD127 and CD57‐expressig subsets in eight HIV infected individuals. Left panels: frequency of each subset out of CD8+ TemRO compared to nine healthy individuals. Statistical significance comparing all groups was determined via one‐way analysis of variance (anova) and Tukey's multiple comparison test and defined as P < 0·05 (black asterisk) and comparing longitudinal patient groups via paired t‐test (red asterisk). (c) Longitudinal analysis of Ki‐67 expression in different CD127/ CD57 subsets of CD8+ TemRO cells of six HIV‐1 infected individuals before and after the start of ART compared to six healthy controls. Statistical significance comparing all groups was determined via one‐way anova and Tukey's multiple comparison test and defined as P < 0·05. (d) Correlation analysis of relative CD127–CD57+ subset size of CD8+ TemRO cells with absolute CD4+ T cell count. Linear regressions and correlations only including untreated (pre‐ART) or treated (ART) patients, respectively. Parameters tested for correlation, statistical significance was defined as P < 0·05. R 2 is a fraction between 0·0 and 1·0 in which 1 presents a perfect fit of the linear regression.
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