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Antiretroviral therapy initiation during primary HIV infection enhances both CD127 expression and the proliferative capacity of HIV-specific CD8+ T cells

Lécuroux, Camillea; Girault, Isabellea; Boutboul, Françoisb; Urrutia, Alejandraa; Goujard, Cécilea; Meyer, Laurencec; Lambotte, Oliviera; Chaix, Marie-Laured; Martinez, Valérieb; Autran, Brigitteb; Sinet, Martinea; Venet, Alainathe ANRS PRIMO Cohort, the ANRS ALT Cohort and the ANRS HIC Study Group

doi: 10.1097/QAD.0b013e32832e6634
BASIC SCIENCE
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Objectives: HIV-specific CD8+ T cells from patients with primary HIV infection (PHI) and after antiretroviral therapy initiation were evaluated for CD127 expression and proliferative capacity and were compared with cells from chronically-infected patients, including long-term nonprogressors and HIV controllers.

Methods: We studied 30 patients with PHI (from the Agence Nationale de Recherche sur le SIDA Primo-infection Cohort) and 33 patients with chronic HIV infection (including nonprogressor patients from the Agence Nationale de Recherche sur le SIDA ALT Cohort and the Agence Nationale de Recherche sur le SIDA HIV Controllers Study Group). HIV-specific CD8+ T cells were identified by costaining with HIV human leukocyte antigen class I pentamers. CD127 expression was assessed by flow cytometry and cell proliferation by carboxyfluorescein succinimidyl ester labeling.

Results: During PHI, most HIV-specific CD8+ T cells coexpressed CD27 and CD45RO, were highly activated, and showed weak Bcl-2 expression. Their CD127 expression was very low and correlated negatively both with HIV RNA and DNA levels and with expression of the activation marker CD38. CD127 expression correlated positively with CD4 cell count, Bcl-2 expression and proliferative capacity. Strong CD127 expression was observed in the two groups of chronically-infected nonprogressors. CD127 expression on HIV-specific CD8+ T cells increased in early-treated PHI patients, reaching levels similar to those observed in nonprogressors. In parallel, these cells acquired strong proliferative capacity. No change in CD127 expression or proliferative potential was observed in untreated patients.

Conclusion: Early antiretroviral therapy initiation enhances CD127 expression on HIV-specific CD8+ T cells, reaching levels similar to those observed in aviremic nonprogressors, and restores their proliferative capacity.

aINSERM U 802, Université Paris-Sud XI, AP-HP Hôpital Bicêtre, Le Kremlin Bicêtre, France

bINSERM U 543, Université Paris VI, AP-HP Hôpital de la Pitié-Salpêtrière, Paris, France

cINSERM U 822, Université Paris-Sud XI, AP-HP Hôpital Bicêtre, Le Kremlin Bicêtre, France

dLaboratoire de Virologie, CHU Necker, Paris, France.

Received 13 March, 2009

Revised 19 May, 2009

Accepted 19 May, 2009

Correspondence to Camille Lécuroux, INSERM U 802, Faculté de Médecine Paris-Sud, Laboratoire d'Immunologie Antivirale Systémique et Cérébrale, 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre, France. Tel: +33 1 49 59 67 20; fax: +33 1 49 59 67 24; e-mail: camille.lecuroux@u-psud.fr

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Introduction

CD8+ T cells play an important role during viral infections. On being activated, naive CD8+ T cells clonally expand, differentiate into effectors, and acquire efficient cytotoxic functions [1,2]. Once the virus has been cleared, most specific CD8+ T cells die by apoptosis whereas the remainders form a pool of memory cells. Memory CD8+ T cells are quiescent, have a long lifespan, and can self-renew in the absence of antigen. When re-exposed to their cognate antigen, they strongly expand and reacquire effector functions.

Interleukin (IL)-7 plays an important role in the generation and maintenance of memory T cells, rescuing them from apoptosis, promoting homeostatic self-renewal [3–5], up regulating anti-apoptotic factor expression [3,6–8] and inactivating pro-apoptotic proteins [9]. The IL-7 receptor α (IL-7Rα or CD127) is needed to trigger the memory pathway, and several studies suggest that IL-7Rα is a marker of memory cells. Cells expressing IL-7Rα also express high levels of the anti-apoptotic molecule Bcl-2, respond to homeostatic cytokines, and have a high proliferative capacity after antigen re-encounter [10,11]. IL-7Rα expression by virus-specific CD8+ T cells is low in human primary cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infections [12], as well as in murine primary lymphocytic choriomeningitis virus (LCMV) infection [11,13,14] and in a variety of chronic infections [15,16]. In their study of mice infected by LCMV, Kaech et al.[11] showed that IL-7Rα/CD127 expression identified effector CD8+ T cells that subsequently differentiated into long-lived memory cells. These CD127+ cells strongly expressed anti-apoptotic molecules and were able to persist and to confer protective immunity after adoptive transfer to naive mice.

Primary HIV-1 infection (PHI) is characterized by marked expansion of HIV-specific CD8+ T cells, which play a key role in initial control of viremia [17–19]. At this stage, most HIV-specific CD8+ T cells are highly activated and are at an intermediate stage of differentiation (CD27+ CD45RO+) generally associated with limited antiviral capacities [20–24]. However, complete viral control is rarely observed after PHI, and persistent viremia is associated with inefficient generation of a memory T cell pool [25–27].

CD127 expression by HIV-specific CD8+ T cells is low in both chronic and early HIV infection, and this is associated with immune activation and viral replication [28–31]. CD127 expression has not been extensively studied during acute HIV infection. The aim of this study was to assess CD127 expression during PHI and to explore its relationship with HIV-specific CD8+ T cell functions (activation, resistance to apoptosis, proliferation) and with the outcome (viral load and clinical progression) of untreated HIV infection. As antiretroviral therapy (ART) initiation during acute HIV infection has been shown to preserve HIV-specific CD4+ and CD8+ T cell responses, at least qualitatively [23,32–35], we also analyzed the effect of early ART initiation on the constitution of an effective CD127+ memory population.

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Materials and methods

Study patients

With their informed consent, we collected samples from 30 patients with PHI enrolled in the French ANRS multicenter Primo-infection (PRIMO) cohort (Agence Nationale de Recherche sur le SIDA, CO 06). Primary infection was defined by HIV RNA positivity and by a negative or emerging antibody response. The decision to begin ART is left to the primary care physicians.

At inclusion, the median plasma HIV RNA level was 4.84 log10 copies/ml [interquartile range (IQR) = 4.08–5.58]. The median CD4+ T cell count was 590/μl (IQR = 412–760), and the median CD8+ T cell count was 930/μl (IQR = 744–1860). Supplemental Table 1 shows the main clinical and biological characteristics of the 30 patients. Sixteen patients received ART at inclusion with a median delay after infection of 42 days, whereas the other 14 patients remained untreated.

We also studied 33 untreated chronically-infected patients. Seven of them had been infected for a median of 4 years and are referred to as viremic progressors. Ten patients had been enrolled in the French ALT cohort ANRS CO 15 (inclusion criteria: HIV infection >8 years and sustained CD4 cell counts >600/μl during the previous 5 years with no ART) and are referred to as viremic nonprogressors. The remaining 16 patients were enrolled in the French HIV-Controllers Study Group [ANRS EP36-HIV controllers (HIC); inclusion criteria: HIV infection >10 years, 90% of plasma HIV RNA values <400 copies/ml with no ART]. The characteristics of these 33 chronically-infected patients are shown in supplemental Table 2.

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Cells and peptides

Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized blood by Ficoll density gradient centrifugation and stored in liquid nitrogen. Human leukocyte antigen typing was done with the complement-dependent microlymphocytotoxic technique (One Lambda, Montpellier, France). IFNγ-enzyme-linked immunosorbent spot assay was used to measure specific responses to peptides corresponding to optimal HIV-cytotoxic T lymphocyte (CTL) epitopes (National Institutes of Health HIV Molecular Immunology Database: http://www.hiv.lanl.gov/content/immunology/tables/optimal_ctl_summary.html).

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Peptide-human leukocyte antigen class 1 multimers

HIV-specific CD8+ T cells were identified by using soluble phycoerythrin (PE)-labeled or allophycocyanin (APC)-labeled peptide-human leukocyte antigen (HLA) class 1 multimers (Proimmune, Oxford, United Kingdom; Beckman Coulter, Villepinte, France) derived from the HIV Gag, Nef, Pol and Env proteins. The following epitopes were used: the HLA-A*0201-restricted peptide ligands SLYNTVATL (Gag 77–85), TLNAWVKVV (Gag 151–159), and ILKEPVHGV (Pol 476–484), the A*0301-restricted peptide ligands RLRPGGKKK (Gag 20–28) and QVPLRPMTYK (Nef 73–82), the A*1101-restricted ligand AVDLSHFLK (Nef 84–92), the A*2402-restricted peptide ligand RYPLTFGWCY (Nef 134–143), the B*0702-restricted peptide ligand IPRRIRQGL (Env 848–856), the B*0801-restricted peptide ligands GEIYKRWII (Gag 259–267) and FLKEKGGL (Nef 90–97), the B*2705-restricted peptide ligand KRWIILGLNK (Gag 263–272), and the B*5701-restricted peptide ligands KAFSPEVIPMF (Gag 162–172), TSTLQEQIGW (Gag 240–249), and QASQDVKNW (Gag 308–316). The following EBV and CMV epitopes were used: the HLA-A*0201-restricted peptide ligands GLCTLVAML (BMLF-1 259–267) and NLVPMVATV (pp65 495–504) and the B*0801-restricted peptide ligand RAKFKQLL (BZLF-1 190–197).

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Flow cytometry

PBMCs were analyzed by four-color or six-color flow cytometry. Samples were first stained with PE-conjugated or APC-conjugated HLA class 1 peptide multimers for 20 min at room temperature, then incubated with labeled specific antibodies for 15 min at 4°C. The following antibodies were used to characterize HIV-specific CD8+ T cells: coupled to fluorescein isothiocyanate (FITC): CD27, CD38, CD45RA and HLA-DR (BD Pharmingen, San Diego, California, USA); coupled to PE: CD127 (R&D Systems, Minneapolis, Minnesota, USA); coupled to phycoerythrin-Texas Red (ECD): CD45RO and CD8 (Beckman Coulter); coupled to phycoerythrin-Cyanin 5 (PC5): CD3 and CD8 (Beckman Coulter); and coupled to peridin chlorophyll protein-cyanin 5.5 (PerCP-Cy5.5): CD8 (BD Pharmingen). To detect intracellular proteins, samples were incubated with anti-Bcl-2-FITC antibodies (BD Pharmingen) for 30 min at room temperature after incubation with fluorescence-activated cell sorting (FACS) permeabilizing solution (BD Biosciences, San Jose, California, USA). Samples were acquired on an Epics XL flow cytometer (Beckman Coulter) or a BD FACSCanto flow cytometer (Becton Dickinson, Franklin Lakes, New Jersey, USA) and analyzed with RXP software (Beckman Coulter).

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Carboxyfluorescein succinimidyl ester proliferation assay

PBMCs were stained with carboxyfluorescein succinimidyl ester 0.35 μmol/l [carboxyfluorescein succinimidyl ester (CFSE); Molecular Probes, Eugene, Oregon, USA] for 10 min at 37°C. After washes, they were cultured for 6 days in Roswell Park Memorial Institute medium containing 10% fetal calf serum and antibiotics, as well as HIV-specific peptides (2 μg/ml). After incubation, the cells were washed and stained as described above (Flow cytometry).

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Statistical analysis

Data were analyzed with GraphPad Prism 5 software (GraphPad Software, Inc., San Diego, California, USA). Variables were compared with nonparametric tests [the Wilcoxon test for paired values and the Mann–Whitney U test or one-way analysis of variance for unpaired values]. Correlations were identified with Spearman's correlation test. P < 0.05 was considered statistically significant.

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Results

HIV-specific CD8+ T cell phenotype during primary HIV infection

HIV-specific CD8+ T cell responses were explored in 50 specificities from the 30 patients (Fig. 1). The cells were at a transient stage of differentiation, as they strongly expressed CD27 (89 ± 14%) and CD45RO (81 ± 15%). They were also highly activated, as shown by their strong expression of the activation markers CD38 (77 ± 24%) and HLA-DR (71 ± 20%). In contrast, they expressed very low levels of CD127 (11 ± 12%) and of the anti-apoptotic molecule Bcl-2 (10 ± 14%). These results suggest that, early during HIV infection, HIV-specific CD8+ T cells are at an intermediate stage of differentiation (CD27+ CD45RO+ CD127-), as well as being highly activated and prone to apoptosis.

Fig. 1

Fig. 1

EBV-specific CD8+ T cells also presented an intermediate stage of differentiation (CD27 expression: 65 ± 19%; CD45RO expression: 74 ± 19%) whereas CMV-specific CD8+ T cells were more differentiated (34 ± 23% and 55 ± 26% for CD27 and CD45RO expression, respectively). Both EBV-specific and CMV-specific CD8+ T cells were moderately activated (48 ± 26% of EBV-specific T cells expressed CD38 and 50% ± 25% HLA-DR versus 44% ± 30% and 26% ± 15% for CD38 and HLA-DR, respectively, on CMV-specific T cells). Both cells expressed low levels of CD127: 26 ± 24% and 26 ± 14% of cells for EBV-specific and CMV-specific T cells, respectively. Accordingly, Bcl-2 expression was low: 12 ± 7% on EBV-specific T cells and 20 ± 14% on CMV-specific T cells.

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Relationships between CD127 expression on HIV-specific CD8+ T cells and virological and immunological parameters during primary HIV infection

As shown in Fig. 2, CD127 expression on HIV-specific CD8+ T cells correlated negatively with plasma viremia (r = −0.33; P = 0.03) and HIV DNA (r = −0.52; P = 0.002) and positively with the CD4 cell count (r = 0.44; P = 0.01).

Fig. 2

Fig. 2

As shown in Fig. 3, CD127 expression correlated negatively with CD38 expression (r = −0.58; P = 0.0004). At the single-cell level, CD127+ HIV-specific CD8+ T cells were less activated than their CD127 counterparts: 53 ± 27% and 80 ± 22% of CD127+ and CD127 cells were CD38+ (P = 0.003), respectively. A similar difference in HLA-DR expression was found (57 ± 25% and 72 ± 27% of CD127+ and CD127 cells, respectively, P = 0.01). We also found a positive correlation between CD127 and Bcl-2 expression (r = 0.67; P = 0.0006), and CD127+ HIV-specific CD8+ cells displayed higher levels of Bcl-2 than their CD127 counterparts (68 ± 26% and 32 ± 34%, respectively, P = 0.004), suggesting the former were more resistant to apoptosis. Finally, CD127 expression on HIV-specific CD8+ T cells correlated positively with these cells' proliferative capacity (r = 0.44; P = 0.04), and CD127+ HIV-specific CD8+ cells displayed stronger expression of CD45RA than their CD127 counterparts (49 ± 24% and 10 ± 14%, respectively; P < 0.0001). Thus, the few CD127+ HIV-specific CD8+ T cells resembled memory-type cells more closely than their CD127 counterparts, in terms of activation status, resistance to apoptosis, and proliferative capacity after stimulation.

Fig. 3

Fig. 3

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Kinetics of CD127 expression and impact of therapy

Baseline CD127 expression was slightly higher on HIV-specific CD8+ T cells in the untreated group (15 ± 15%) than in the treated group (7 ± 8%), in keeping with the less severe virological and immunological status in the former group (see Supplemental Table 1). Five untreated patients were further identified and defined as rapid progressors), as their CD4+ cell counts fell (or remained) below 350/μl during the first year of infection. Baseline CD127 expression by HIV-specific CD8+ T cells was lower in these five rapid progressor patients than in the other untreated patients (5 ± 3% versus 22 ± 16%, P = 0.003) (Fig. 5a). In the 14 untreated patients, CD127 expression on HIV-specific CD8+ T cells remained low at M6 (17 ± 12%), M12 (14 ± 12%), and M24 (23 ± 6%) (P > 0.05 versus baseline, all comparisons) (Fig. 4), with levels comparable to those observed in seven untreated viremic progressors (Vir+ Prog+) infected for a median of 48 months (24 ± 18%) (Fig. 5a).

Fig. 4

Fig. 4

Fig. 5

Fig. 5

In contrast, in treated patients, CD127 expression on HIV-specific CD8+ T cells increased over time, to 28 ± 15% at M6, 44 ± 16% at M12, and 48 ± 24% at M24 (M6 versus baseline, P < 0.05; M12 and M24 versus baseline, P < 0.001) (Fig. 4). Treatment initiation during the chronic phase of HIV infection only partially restores CD127 expression on virus-specific T cells [28]. We therefore compared CD127 expression after treatment initiation during PHI with that observed in two cohorts of untreated chronically HIV-infected patients with favorable outcomes. Expression in the treated group was similar to that observed in the viremic nonprogressors (mean expression of 13 determinations in 10 patients: 52 ± 23%) and in the aviremic nonprogressors (mean expression of 27 determinations in 16 patients: 67 ± 21%) (Fig. 5a).

Expression of CD127 also increased on EBV-specific and CMV-specific CD8+ T cells in treated patients, whereas only minimal changes from baseline were observed in the untreated group.

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High-level CD127 expression on HIV-specific CD8+ T cells is associated with increased proliferative capacity after early therapy

A strong proliferative capacity of HIV-specific CD8+ T cells is a hallmark of HIV controllers [36]. We therefore examined whether the marked increase in CD127 expression observed after early therapy was associated with an increase in proliferative capacity. Proliferative capacity was generally low during PHI, as reflected by low percentages of CFSELow HIV-specific CD8+ T cells (37 ± 39%), especially in the rapid progressor subgroup (14 ± 32%), and no change was seen in the followed untreated patients (28 ± 32%) (Fig. 5b). In contrast, HIV-specific CD8+ T cells from early-treated patients proliferated strongly in response to HIV peptides (72% ± 24%), at levels similar to those seen in aviremic nonprogressors (67 ± 25% of CFSELow HIV-specific CD8+ T cells). Proliferative capacity was not determined in the Vir+ Prog group (Fig. 5b). Finally, we found a significant correlation between CD127 expression and the proliferative capacity of HIV-specific CD8+ T cells in the overall population (r = 0.37, P = 0.003) (Fig. 5c).

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Discussion

We report an extensive analysis of IL-7Rα (CD127) expression on HIV-specific CD8+ T cells in acutely and chronically-infected patients with different clinical status. Most analyses of CD127 expression during HIV infection have been performed during the chronic phase or with global CD8+ T cells. Initiation of ART during primary HIV infection (PHI) increases CD127 expression on HIV-specific CD8+ T cells and restores their proliferative capacity reaching levels similar to those observed in aviremic nonprogressors.

We first investigated CD127 expression by HIV-specific CD8+ T cells during PHI. These cells were highly activated and at an intermediate stage of differentiation, and few expressed the memory marker CD127 or the anti-apoptotic molecule Bcl-2. This confirms and extends the results of Sabbaj et al.[37] who reported a low CD127 expression in few patients during PHI. Indeed, this phenotype is also found in other primary infections as CMV-specific and EBV-specific CD8+ T cells express CD27 and CD45RO [38] but not CD127 [12]. IL-7R expression is also low on HBV-specific CD8+ T cells [15,16] and on hepatitis C virus (HCV)-specific CD8+ T cells [39] during the acute phase of these infections. Kaech et al.[11] found that most virus-specific CD8+ T cells were CD127 during the acute stage of LCMV infection. This phenotype was associated with characteristics of potent effector cells [11,29]. Together, these findings support the idea that memory effector cells predominate during PHI and result from the expansion of CD127 CD8+ T cells.

Several studies have shown that CD127 expression on total CD8+ T cells correlates negatively with HIV RNA levels and positively with the CD4 cell count during the chronic phase of HIV infection [28–31]. The relationships between CD127 expression on HIV-specific CD8+ T cells and immunovirological markers are more controversial [37,40]. We found that low CD127 expression on HIV-specific CD8+ T cells was associated with a high level of viral replication and a low CD4 cell count. Moreover, we found a negative correlation between CD127 expression on HIV-specific CD8+ T cells and HIV DNA levels that has not previously been reported.

Strong generalized immune activation is commonly described during acute HIV infection [22,41]. Studies of simian models have highlighted the role of immune activation in CD4 cell depletion and immunopathogenesis in HIV infection [42–44]. We and others [22,41] have shown that HIV-specific CD8+ T cells are strongly activated during PHI. We found a negative correlation between CD127 expression and CD38 expression on HIV-specific CD8+ T cells. This may simply reflect the reported relationship between immune activation and viral load [45,46]. However, at the single-cell level, we found that CD127+ HIV-specific CD8+ T cells were less activated than their CD127 counterparts. This high level of activation may also be responsible for a generalized nonspecific bystander phenomenon, as demonstrated by increased levels of CD38 and HLA-DR expression on EBV-specific and CMV-specific CD8+ T cells, both in the present study and elsewhere [22]. This may explain the reduced CD127 expression that we observed during PHI on these non-HIV-specific CD8+ T cells as also observed by Paiardini et al.[29] but not by Sabbaj et al.[37].

In previous studies, CD127 expression was found to be associated with a memory-like phenotype, whereas the absence of CD127 expression was associated with a more differentiated effector phenotype [11,12,29,30,47]. However, there is no consensus method for the use of markers that are able to distinguish between memory-like and effector-like CD8+ T cells. It might be more informative to evaluate memory-associated functions such as resistance to apoptosis and proliferation upon antigen re-exposure. Here, we found that high CD127 expression on HIV-specific CD8+ T cells was associated with higher expression of the anti-apoptotic marker Bcl-2 and with a higher capacity to proliferate after stimulation. Here again, separate analysis of the CD127+ and CD127 HIV-specific CD8+ T subsets confirmed that CD127+ HIV-specific CD8+ T cells express higher levels of Bcl-2 than their CD127 counterparts. Similar results have been reported by van Leeuwen et al.[12] in CMV infection, confirming the results of Paiardini et al.[29] in HIV infection. Stronger CD127 expression on HIV-specific CD8+ T cells was also associated with a higher capacity to proliferate in response to antigenic stimulation and probably with better IL-2-secreting CD4+ T cell responses [48,49]. Interestingly, the few CD127+ HIV-specific CD8+ T cells observed during PHI were mostly CD27+ CD45RA+. Antigen-specific CD45RA+ CD8+ T cells have been identified in various contexts, including HIV infection, and have been shown to display memory characteristics [23,50–52].

Together, these results show that, during PHI, HIV-specific CD8+ T cells have weak CD127 expression, are highly activated, and have characteristics of effector cells. However, a small subset of HIV-specific CD8+ T cells express CD127, are less activated, and show lower expression of effector markers. This tends to confirm that these CD127+ HIV-specific CD8+ T cells may represent effector CD8+ T cells that subsequently differentiate into memory cells, as suggested by Kaech et al.[11].

Early treatment initiation during PHI has been shown to preserve HIV-specific CD4+ T cell responses and to rapidly attenuate the associated immune activation [41]. Both phenomena are known to be associated with the development of efficient memory CD8+ T cells. The timing of ART initiation appears to be essential for the development of an effective CD127+ memory population [28,29,37,40,47,53].

Two different profiles of nonprogression have been described in HIV infection: first, patients with immunological control (stable CD4+ cell counts) and long-term nonprogression, who are referred to as ‘viremic nonprogressors’; and second, patients with spontaneous virological control, who are referred to here as ‘aviremic nonprogressors’ and elsewhere as ‘HIV or elite controllers’. Both situations are associated with efficient CD8+ T cell responses.

We found a high level of CD127 expression on HIV-specific CD8+ T cells in 26 nonprogressors (total of 40 specificities tested), regardless of their viremic status. In contrast, Sabbaj et al.[37] reported low CD127 expression on HIV-specific CD8+ T cells from HIV controllers. However, they used IFN-γ production to identify specific CD8+ T cells instead of pentamers; the peptide used to induce IFN-γ production could have activated the cells and contributed to CD127 down regulation [14]. Early therapy during PHI leads to a rapid increase in CD127 expression to levels close to those observed in nonprogressors. In contrast, no increase in CD127 expression was observed in untreated patients during follow-up.

In HIV controllers, HIV-specific CD8+ T cells have also been defined by their particular capacity to proliferate [36,54]. We show here that HIV-specific CD8+ T cells of patients treated early during PHI display a high capacity to expand, similar to that seen in aviremic nonprogressors.

Taken together, these results suggest that early treatment initiation promotes the development of an effective CD127+ memory pool similar to that seen in nonprogressors and endowed with high proliferative capacity.

In untreated individuals, constant activation of HIV-specific CD8+ T cells by sustained viral replication, together with deficient CD4+ T cell help, might compromise CD127 expression and push CD8+ T cells toward an effector phenotype rather than a memory phenotype. This is particularly the case in rapid progressors in whom we observed a very low level of CD127 expression associated with little or no proliferative capacity. Because of the tight links between viral load, activation status and CD127 expression, multivariate analysis of larger populations would be necessary to determine whether analysis of CD127 expression in the acute phase of HIV infection might help to predict the risk of clinical progression.

In summary, the persistence of viremia in most untreated HIV-infected individuals leads to permanent differentiation of HIV-specific CD8+ T cells toward an effector phenotype and to a concurrent defect in efficient memory T cell differentiation, as shown by CD127 expression status. This phenomenon is reversed when viral replication is inhibited by ART, especially when treatment is started during the acute infection. Further studies are needed to determine whether these treatment-induced changes in HIV-specific immune responses are associated with long-term clinical benefits.

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Acknowledgements

This work was supported in part by institutional grants from Institut National de la Santé et de la Recherche Médicale, Agence Nationale de Recherches sur le SIDA et les hépatites virales, and Sidaction. C.L. is supported by grants from Ministère de l'Enseignement Supérieur et de la Recherche, and Sidaction.

C.L. performed the research, analyzed data, and wrote the article. M.S. and A.V. managed and designed the research and participated in writing the article. B.A. designed the research and participated in data centralization and coordination of the French ALT cohort (Agence Nationale de Recherche sur le SIDA, CO-15). C.G., O.L. and L.M. participated in data centralization and coordination of the French PRIMO cohort and HIV-Controllers Study Group (ANRS, CO-6 and EP36). I.G. and A.U. participated in performing the research and analyzing data. F.B., M.-L.C. and V.M. participated in performing the research.

The authors thank Christiane Deveau and Faroudy Boufassa for the coordination of the French PRIMO cohort and the French HIV-Controllers Study Group as well as the clinicians and patients from all the participating centers of the French PRIMO cohort, the French ALT cohort, and the EP36-HIC study group (Agence Nationale de Recherches sur le SIDA, CO 06-PRIMO Cohort, AC51-ALT Cohort and EP36-HIC Study Group). We also thank David Young for editorial assistance.

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Fig. 1

Fig. 1

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Keywords:

antiretroviral therapy; CD127; HIV controllers; memory CD8 T cells; primary HIV infection

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