HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity

Souheil-Antoine Younes, Bader Yassine-Diab, Alain R Dumont, Mohamed-Rachid Boulassel, Zvi Grossman, Jean-Pierre Routy, Rafick-Pierre Sekaly, Souheil-Antoine Younes, Bader Yassine-Diab, Alain R Dumont, Mohamed-Rachid Boulassel, Zvi Grossman, Jean-Pierre Routy, Rafick-Pierre Sekaly

Abstract

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma. Longitudinal analysis of HIV epitope-specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-gamma-producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2-producing CD4+ T cells and that IFN-gamma only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.

Figures

Figure 1.
Figure 1.
Ability of HIV-specific CD4+ T cells to proliferate in vitro. (a) Comparison between aviremic (12C, 12B, and 11C) and viremic (111, 112, and 113) patients for the ability of CD4+ T cells to proliferate in vitro. PBMCs from aviremic and viremic patients were labeled with CFSE and stimulated for 6 d with the selected Gag peptides G067 (WIILGLNKIVRMYSP), G076 (YKTLRAEQASQEVKN), G065 (PVGEIYKRWIILGLN), G054 (DRVHPVHAGPIAPGQ), and G008 (YKLKHIVWASRELER). The numbers indicated in each quadrant are the percentage of CD3+ CD4+ CFSElow T cells. NS, media stimulation; SEA, staphylococcal enterotoxin. The data are representative of five different experiments. (b) Proliferative response of CFSE-labeled PBMCs from aviremic (•) and viremic (○) patients to HIV, CMV lysate, and SEA antigen. Two peptides (Gag and Nef peptides) were chosen per patient for their ability to induce the highest percentage of CFSElow CD4+ T cells in both aviremic and viremic patients. The sequences of the peptides are listed in Tables II and III. Median percentage of CFSElow HIV-1 CD4+ T cells in aviremic patients is 9.2% (n = 20; range, 6–20%), whereas the median response in viremic patients is 0.3% (n = 16; range, 0.2–0.5%). CMV lysate median CD4+ T cell responses are 11% in aviremic (n = 10; range, 5–30%) and 12.5% in viremic patients (n = 8; range, 5–32%). Median CD4+ T cells responses with SEA stimulation are 50% in aviremic (n = 8; range, 44–60%) and 47.5% in viremic patients (n = 8; range, 40–60%). Statistical significance is determined by the exact Mann-Whitney test.
Figure 2.
Figure 2.
Four-parameter FACS® analysis of epitope-specific CD4+ T cells in aviremic and viremic patients. (a and b) Detection of epitope-specific CD4+ T cells by intracellular IL-2 and IFN-γ staining of PBMCs from aviremic (12C) and viremic (111) patients. PBMCs were stimulated with 10 μg/ml of the indicated peptides or 200 ng/ml SEA, or unstimulated (NS) for 12 h in the presence of Brefeldin A. Numbers in each quadrant represent the frequency of CD69+ cytokine+. (c) Frequency of CD69+ IL-2+ HIV-specific CD4+ T cells (○) or CD69+ IFN-γ+ (•) after 12 h of peptide stimulation of PBMCs from aviremic and viremic patients. Single epitope responses (two per patient) are depicted. Data are derived from Tables II and III. Statistical significance is determined by the exact Mann-Whitney test. 5 × 104–105 CD4+ T cell gated events are shown. Data are representative of three different experiments.
Figure 3.
Figure 3.
Correlation between the frequency of HIV-1 epitope-specific CD4+ T cells monitored by IL-2 (○) or IFN-γ cytokine (•) deleted after 12 h and the frequency of CFSElow CD4+ T cells after 6-d in vitro proliferation in aviremic (a and b) and viremic (c) patients. Statistical significance of each correlation was calculated using Spearman test. (d) IL-2 restores the proliferation of IFN-γ+ IL-2− HIV-specific CD4+ T cells. PBMCs from viremic patients (111, 112, and 113) were labeled with CFSE and stimulated for 6 d using a pool of HIV-specific peptides (10 overlapping peptides spanning the entire immunodominant region GSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSIL) with or without 10 U/ml of IL-2. The numbers in each quadrant represent percentages of dividing T cells. 2–3 × 104 events gated on live CD3+ CD4+ lymphocytes were collected and analyzed.
Figure 3.
Figure 3.
Correlation between the frequency of HIV-1 epitope-specific CD4+ T cells monitored by IL-2 (○) or IFN-γ cytokine (•) deleted after 12 h and the frequency of CFSElow CD4+ T cells after 6-d in vitro proliferation in aviremic (a and b) and viremic (c) patients. Statistical significance of each correlation was calculated using Spearman test. (d) IL-2 restores the proliferation of IFN-γ+ IL-2− HIV-specific CD4+ T cells. PBMCs from viremic patients (111, 112, and 113) were labeled with CFSE and stimulated for 6 d using a pool of HIV-specific peptides (10 overlapping peptides spanning the entire immunodominant region GSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPTSIL) with or without 10 U/ml of IL-2. The numbers in each quadrant represent percentages of dividing T cells. 2–3 × 104 events gated on live CD3+ CD4+ lymphocytes were collected and analyzed.
Figure 4.
Figure 4.
Six color FACS® analysis of HIV-specific CD4+ T cells in aviremic and viremic patients. (a) Representative pseudo color plots of phenotypic analysis of G067-specific CD4+ T cells in PBMCs from aviremic (12C) and viremic (111) patients. Numbers above 0.01% in each plot were considered positive. Patients' PBMCs were stimulated with G067 peptide for 12 h in the presence of Brefeldin A and stained with biotinylated anti-CCR7 followed by streptavidin PE-Cy7, anti-CD4 APC-Cy7. Anti–IL-2 PE, anti–IFN-γ APC, and anti-CD69 FITC were added after fixation/permeabilization of the cells. 3 × 105 gated CD4+ T cell events are shown. (b) Schematic representation of IL-2+ and/or IFN-γ+ CD4+ T cell distributions and the expression of CCR7/CD45RA in three aviremic and three viremic patients after stimulation with G067 peptide. Data are representative of three different experiments.
Figure 4.
Figure 4.
Six color FACS® analysis of HIV-specific CD4+ T cells in aviremic and viremic patients. (a) Representative pseudo color plots of phenotypic analysis of G067-specific CD4+ T cells in PBMCs from aviremic (12C) and viremic (111) patients. Numbers above 0.01% in each plot were considered positive. Patients' PBMCs were stimulated with G067 peptide for 12 h in the presence of Brefeldin A and stained with biotinylated anti-CCR7 followed by streptavidin PE-Cy7, anti-CD4 APC-Cy7. Anti–IL-2 PE, anti–IFN-γ APC, and anti-CD69 FITC were added after fixation/permeabilization of the cells. 3 × 105 gated CD4+ T cell events are shown. (b) Schematic representation of IL-2+ and/or IFN-γ+ CD4+ T cell distributions and the expression of CCR7/CD45RA in three aviremic and three viremic patients after stimulation with G067 peptide. Data are representative of three different experiments.
Figure 5.
Figure 5.
Longitudinal analysis of epitope-specific CD4+ T cells in three aviremic (11C, 12C, and 13 C) and three viremic (111, 112, and 113) patients by intracellular IL-2 and IFN-γ staining and a CFSE-based proliferation assay. (a) Pseudo color plots from aviremic patients stimulated with G067 peptide or G065 and G076 peptide showing the detection of IL-2/IFN-γ and IL-2 1 yr (Time 1) and 4–5 yr (Time 2) after HAART initiation. (b) Pseudo color plots showing the frequency of G067-specific CD4+ T cells from viremic patients by IL-2/IFN-γ ICS at time points before therapy (Time 1), 1 yr (Time 2), and 6 yr (Time 3) after therapy initiation. Numbers in each quadrant represent the percentage of IL-2– and/or IFN-γ–producing CD4+ T cells after stimulation with G067 peptide. Data are representative of three different experiments. Media stimulation was ≤0.01% in all experiments. Between 5 × 104 and 2 × 105 events, gated on CD4+ T cells, were collected and analyzed. (c) Pseudo color plots showing the proliferative responses of G067-specific CD4+ T cells at the same time points as in b. 2–5 × 104 gated CD3+ CD4+ T cells were collected after 6-d in vitro incubation and analyzed.
Figure 6.
Figure 6.
Alternative differentiation schemes describing the impact of HIV viremia on the size of memory/effector CD4+ T cell pools. (a) According to an extension of a general differentiation scheme proposed for CD8 T cells by Kaech et al. (reference 46), HIV-specific central memory CD4+ T cells (Tcm) are derived in aviremic patients from effectors (Tem1) elicited during the acute phase of the infection. Transient activation episodes and IL-2 production–dependent self-renewal would facilitate maintenance of a stable steady state of this memory pool, in equilibrium with the Tem1 pool, after viremia has been controlled. When viremia persists, naive CD4+ T cells are constantly recruited and differentiate into effectors (Tem1). Constant antigenic stimulation prevents the differentiation of these effectors into Tcm. Instead, they differentiate into more differentiated cells, Tem2, which lack the capacity to produce IL-2 and to self-renew, but are able to produce IFN-γ. (b) Alternatively, the order of differentiation is always from naive to Tcm to Tem, as proposed by Lanzavecchia and Sallusto (reference 45). In aviremic patients, Tcm and Tem1 are maintained, as in the other model, by self-renewal and occasional activation and differentiation events (limited ongoing division counters the slow rate of death in the population). In the viremic patients, activation of HIV-specific naive and resting memory cells is enhanced, but according to the “balance of growth and differentiation” model (see Discussion), accumulation of Tcm and Tem1 memory cells through self-renewal division is prohibited because these proliferating cells are preferentially induced to differentiate into the IFN-γ only–producing Tem2 cells. The relative rates of self-renewal and differentiation are crudely reflected in the figure by the thickness of the arrows representing cellular flow. The relative size of the different pools is indicated by the size of the circles representing these pools.

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