Potential role for HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppression and cytotoxicity in HIV controllers.

BACKGROUND: HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38-/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status. MATERIALS AND METHODS: We compared CD38-/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. RESULTS: Compared to CD38+/HLA-DR+ cells, CD38-/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134-462] vs 638 [307-747], P = 0.001), higher frequency of polyfunctional cells (15% [7%-33%] vs 21% [16%-43%], P = 0.0003), greater proliferative capacity (0-fold [0-2] vs 3-fold [2]-[11], P = 0.007), and higher cytotoxicity in vitro (7% [3%-11%] vs 13% [6%-22%], P = 0.02). The CD38-/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations. CONCLUSIONS: These data highlight the role of CD38-/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies.

Both HLA-B*57 and plasma HIV RNA levels contribute to the HIV-specific CD8+ T cell response in HIV controllers.

CD8(+) T cell responses are thought to play an important role during HIV infection, particularly in HIV controllers (HIC) in whom viral replication is spontaneously controlled without any treatment. We have demonstrated that CD8(+) T cells from these subjects are able to suppress viral replication in vitro. In parallel, HIV-specific CD8(+) responses were shown to be strong and of high quality, with proliferative abilities and cytotoxic capacities, in HIC. The HLA-B*57 allele, which is associated with a better clinical outcome in HIV infection, is overrepresented in HIC. However, we showed that these patients constitute a heterogeneous group that includes subjects who present weak suppression of viral replication in vitro and HIV-specific responses. We performed an extensive study of 101 HIC (49 HLA-B*57(+) and 52 HLA-B*57(-)) to determine the impact of HLA-B*57 on the HIV-specific CD8(+) response. The HLA-B*57-restricted response displayed better qualitative features, such as higher functional avidity, higher proliferation capacity, and a higher level of cytokine production, than responses not restricted by HLA-B*57. However, the highest frequencies of HIV-specific CD8(+) T cells were observed only in a subset of HLA-B*57(+) subjects. They were tightly associated with the ability to suppress viral replication in vitro. In contrast, the subset of HLA-B*57(+) subjects with a weak ability to suppress viral replication had significantly lower ultrasensitive viral loads than all the other groups of controllers. In conclusion, both HLA-B*57 and the amount of ultrasensitive viral load seem to play a role in HIV-specific CD8(+) T cell responses in HIC.

Acute plasma biomarkers of T cell activation set-point levels and of disease progression in HIV-1 infection.

T cell activation levels, viral load and CD4(+) T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-ß1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4(+) T cell counts at set-point and capable to predict 30% of the CD4(+) T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4(+) T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4(+) T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4(+) T cell counts or viremia levels.

HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy.

BACKGROUND: The occurrence of viral control after interruption of an antiretroviral treatment (ART) initiated during primary HIV-1 infection (PHI) is rare and the frequency and predictive factors of such a control are unknown. METHODS: Within the French ANRS PRIMO Cohort, 164 patients interrupted ART initiated during PHI. We compared patients whose viral load (VL) remained undetectable (<50 copies/ml) or low (50-500 copies/ml) 1 year after ART interruption to those who evidenced a rapid viral rebound. RESULTS: After ART interruption, VL remained undetectable for a median time of 4.5 years in 14 patients ('post-ART controllers') and low in another 14 patients for a median time of 1.5 years. Post-ART controllers also maintained higher CD4(+) T-cell counts compared to other patients. Female gender, a high CD4(+) T-cell count and low VL during PHI, and a high CD4(+) T-cell count and low HIV DNA levels at interruption, were associated with post-ART HIV control. Treatment characteristics did not differ between controllers and non-controllers. Post-ART controllers had lower specific CD8(+) T-cell frequencies and CD8(+) T-cell activation on ART and after ART interruption than non-controllers. CONCLUSIONS: Few patients maintain very low VL after interruption of treatment initiated during PHI. Early patient characteristics were the main factors of viral control, although early initiation of ART and the effect of ART on reservoir might contribute to control.

Early and long-lasting alteration of effector CD45RA(-)Foxp3(high) regulatory T-cell homeostasis during HIV infection.

Regulatory T-cell (Treg) quantification in human immunodeficiency virus (HIV) infection remains ill defined because of the lack of reliable specific markers to identify human Tregs and the diversity of clinical stages of HIV infection. Using a recently described Treg identification strategy based on CD45RA and Foxp3 expression, we performed an extensive quantification of total, naive (CD45RA(+)Foxp3(low)), and effector (CD45RA(-)Foxp3(high)) Tregs in different contexts of HIV infection: primary HIV infection, long-term viremic patients, aviremic patients treated with highly active antiretroviral therapy, and HIV controllers. We showed that although total Treg percentages were mildly affected by HIV infection, Treg absolute numbers were significantly reduced in all groups studied. We demonstrated that although naive Treg numbers were essentially preserved, effector Tregs were consistently affected during HIV infection. Finally, we demonstrated that effector but not total or naive Treg numbers were negatively correlated with the magnitude of HIV-specific CD8 T-cell responses.

Spontaneous control of viral replication during primary HIV infection: when is "HIV controller" status established?

Eight patients in the ANRS PRIMO cohort experienced early spontaneous viral control. Viral control was established a median of 6.2 months after primary human immunodeficiency virus type 1 infection and lasted a median of 4.1 years. Seven of the patients initially had detectable viral replication. For 4 patients, viral control was lost during follow-up.

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

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.

Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses.

"HIV controllers" (HICs) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This spontaneous viral control in HICs is usually associated to strong functional HIV-specific CD8(+) T cell responses. Accordingly, we have recently shown that CD8(+) T cells from HICs strongly suppress ex vivo HIV-1 infection of autologous CD4(+) T cells, suggesting a crucial role of this response in vivo. Knowledge of the mechanisms underlying the CD8(+) T cell antiviral activity might help to develop effective T cell-based vaccines. In the present work, we further characterized the HIV-suppressive capacity of CD8(+) T cells in 19 HICs. CD8(+) T cells from 14 of the 19 HICs showed strong HIV-suppressive capacity ex vivo. This capacity was stable over time and was partially effective even on other primate lentiviruses. HIV-suppressive capacity of CD8(+) T cells correlated strongly with the frequency of HIV-specific CD8(+) T cells, and in particular of Gag-specific CD8(+) T cells. We also identified five HICs who had weak HIV-suppressive CD8(+) T cell capacities and HIV-specific CD8(+) T cell responses. Among these five HICs, at least three had highly in vitro replicative viruses, suggesting that the control of viremia in these patients is not due to replication-defective viruses. These results, on the one hand, suggest the importance of Gag responses in the antiviral potency of CD8(+) T cells from HICs and, on the other hand, propose that other host mechanisms may contribute to restraining HIV infection in HICs.

Identification of a particular HIV-specific CD8+ T-cell subset with a CD27+ CD45RO-/RA+ phenotype and memory characteristics after initiation of HAART during acute primary HIV infection.

CD8(+) T cells play an important role in controlling viral infections. Defective CD8(+) T-cell responses during HIV infection could contribute to viral persistence. Early initiation of highly active antiretroviral therapy during acute primary HIV infection helps to preserve HIV-specific immune responses. Here, we describe a particular CD27(+) CD45RO(-)/RA(+) HIV-specific CD8(+) T cell in participants treated early during the primary infection. These cells, which were present at a very low frequency during primary HIV infection, increased markedly after early treatment, whereas their frequency remained unchanged in untreated participants and in participants treated later. These nonnaive antigen-experienced cells are in a resting state and have characteristics of long-lived memory cells. They also possess direct effector capabilities, such as cytokine production, and are able to proliferate and to acquire cytotoxic functions on reactivation. Our results suggest that these HIV-specific CD27(+) CD45RO(-)/RA(+) CD8(+) T cells, observed when early viral replication is inhibited, form a pool of resting cells with memory characteristics.

Rapid CD4+ cell decrease after transient cART initiated during primary HIV infection (ANRS PRIMO and SEROCO cohorts).

OBJECTIVE: To modelize the rate of CD4 cell count decline and its determinants after cessation of combination antiretroviral therapy (cART) started during primary HIV infection (PHI) and compare it with never-treated patients. METHODS: Kinetics of CD4 counts were analyzed on the square root scale by using a mixed-effects model in 170 patients who received cART during PHI from the Primary Infection (PRIMO) cohort and 123 never-treated patients from the Seroconverters (SEROCO) cohort. RESULTS: After cART interruption in the PRIMO cohort, the CD4 cell count fell rapidly during the first 5 months and more slowly thereafter. The timing of treatment initiation had no influence on the rate of CD4 cell decline. In contrast, a larger increase in CD4 cell counts during cART was associated with a steeper decline and a larger loss of CD4 cells after treatment interruption. The mean CD4 cell loss 3 years postinterruption was 383 cells per microliter. In the SEROCO cohort, the CD4 T-cell decline was less steep (3-year CD4 loss 239 cells/microL). As a result, the mean CD4 cell counts were similar (416 cells/microL) 3 years after cART interruption (PRIMO) or after infection (SEROCO). CONCLUSIONS: These data question the benefit of a limited course of cART even when initiated within 3 months after PHI diagnosis.

HIV controllers: how do they tame the virus?

HIV controllers are rare, chronically HIV-1-infected patients in whom viral replication is undetectable in the absence of antiretroviral treatment. Most such patients are nonetheless infected by replication-competent viruses. An effective, multifunctional HIV-specific CD8(+) T-cell response is thought to be central to viral control in these individuals. The mechanisms underlying this spontaneous control of HIV infection and the particular characteristics of the CD8(+) T-cell response in HIV controllers are the focus of intensive investigations, because they should help to unravel the pathogenesis of AIDS and to provide new clues for the design of effective vaccine strategies. In this review, we examine recent findings from these studies.

Preserved central memory and activated effector memory CD4+ T-cell subsets in human immunodeficiency virus controllers: an ANRS EP36 study.

Human immunodeficiency virus (HIV) controllers are rare individuals who spontaneously control HIV type 1 replication for 10 years or more in the absence of antiretroviral treatment. In the present study, HIV controllers (n = 11) maintained potent HIV-specific CD4 responses in spite of very low antigenic loads. Their CD4+ central memory T (T(CM)) cells were characterized by near-normal numbers and preserved interleukin-2 (IL-2) secretion in response to HIV antigens and uniformly high expression of the survival receptor IL-7 receptor alpha (IL-7Ralpha). Controllers expressed CCR7 at higher levels than uninfected controls, suggesting differences in T(CM)-cell homing patterns. CD4+ effector memory T (T(EM))-cell responses were polyfunctional in HIV controllers, while IL-2 secretion was lost in viremic patients. Cytokine production was three times higher in controllers than in treated patients with undetectable viral loads, suggesting an intrinsically more efficient response in the former group. The total CD4+ T(EM)-cell pool underwent immune activation in controllers, as indicated by increased HLA-DR expression, decreased IL-7Ralpha expression, a bias towards gamma interferon production upon polyclonal stimulation, and increased macrophage inflammatory protein 1beta secretion associated with chronic CCR5 down-regulation. Thus, HIV controllers showed a preserved CD4+ T(CM)-cell compartment and signs of potent functional activation in the CD4+ T(EM)-cell compartment. While controllers did not show the generalized immune activation pattern associated with disease progression, they had signs of immune activation restricted to the effector compartment. These findings suggest the induction of an efficient, nondetrimental type of immune activation in patients who spontaneously control HIV.

HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype.

Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been associated with a strong, multifunctional specific CD8(+) T cell response. However, no direct link between this immune response and the control of viremia has so far been provided. We investigated parameters of specific CD8(+) T cell response and in vitro susceptibility to HIV-1 infection in 11 HIC. We found high frequencies of HIV-specific CD8(+) T cells. Interestingly, these cells expressed the activation marker HLA-DR but not CD38. This unique phenotype differentiates HIV-specific CD8(+) T cells from HIC and noncontroller subjects and likely reflects a high potential to expand upon exposure to antigen and a capacity to exert effector functions. Accordingly, although CD4(+) T cells from HIC were fully susceptible to HIV-1 superinfection, their CD8(+) T cells effectively suppressed HIV-1 infection. Remarkably, this potent anti-HIV activity was observed without prior stimulation of CD8(+) T cells. This activity was not mediated by secreted inhibitory factors but was due to the elimination of infected CD4(+) T cells and was observed only with autologous CD4(+) T cells, indicating an HLA-restricted cytotoxic mechanism. This constitutive antiviral capacity of CD8(+) T cells could account for the control of viral replication in HIC.

CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV type 1 infection in untreated patients.

BACKGROUND: Treatment initiation at the time of primary human immunodeficiency virus (HIV) type 1 (HIV-1) infection has become less frequent in recent years. METHODS: In the French prospective PRIMO Cohort, in which patients are enrolled at the time of primary HIV-1 infection, 30% of the 552 patients recruited during 1996-2004 did not start receiving antiretroviral treatment during the first 3 months after diagnosis. We analyzed the patients' clinical and immunological outcomes and examined potential predictors of disease progression. Progression was defined as the occurrence of an acquired immunodeficiency syndrome (AIDS)-related clinical event or a CD4 cell count <350 cells/mm3. RESULTS: Fifty-six (34%) of the untreated patients experienced immunological progression during a median duration of follow-up of 24 months, and 1 of these patients had an AIDS-related event. The estimated risks of progression were 25%, 34%, and 42% at 1, 2, and 3 years after enrollment, respectively. Compared with patients who did not have progression, those with progression had significantly lower CD4 cell counts at diagnosis (455 vs. 738 cells/mm3), higher plasma HIV RNA levels (4.9 vs. 4.5 log10 copies/mL), and higher HIV DNA levels (3.3 vs. 3.0 log(10) copies/10(6) peripheral blood mononuclear cells [PBMCs]). All 3 parameters were significantly associated with progression in univariate analysis. In multivariate analysis, only the CD4 cell count and HIV DNA level were independently predictive of disease progression (relative hazard for CD4 cell count, 1.84 per decrease of 100 cells/mm3; relative hazard for HIV DNA level, 2.73 per increase of 1 log(10) copies/10(6) PBMCs). CONCLUSIONS: Both a low initial CD4 cell count and a high HIV DNA level are predictive of rapid progression of untreated primary HIV-1 infection. Affected patients may therefore benefit from close clinical and laboratory monitoring and/or early administration of treatment.

Type I interferon production is profoundly and transiently impaired in primary HIV-1 infection.

BACKGROUND: Successful immunological control of human immunodeficiency virus (HIV) infection is achieved only in rare individuals. Plasmacytoid dendritic cells (DCs) are mostly responsible for the production of strong antiviral factors--that is, type I interferons (IFNs)--in response to viruses. Their natural IFN production is impaired in chronic HIV infection, in correlation with viral load and disease progression, but it has not been tested during the critical stage of primary infection, when a balance is set between host immune responses and viral replication. METHODS: We longitudinally studied 26 patients during the primary stage of HIV infection. Fifteen patients received highly active antiretroviral therapy (HAART) for 12 months. RESULTS: At the time of inclusion into the cohort, median type I IFN production in response to herpes simplex virus type 1 stimulation was dramatically impaired in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients, compared with that in PBMCs from 31 uninfected donors (180 vs. 800 IU/mL; P<.0001). Median circulating plasmacytoid DC counts were also significantly decreased (7300 vs. 13,500 cells/mL; P=.001). Twelve months later, IFN production returned to normal, and the data suggest that HAART may help in the recovery of IFN production by plasmacytoid DCs. CONCLUSIONS: These data underline the potential for early antiretroviral treatment and IFN- alpha treatment to enhance viral control in a larger proportion of patients during the critical stage of primary infection.

Does transient HAART during primary HIV-1 infection lower the virological set-point?

OBJECTIVES: To assess the influence of patient characteristics, treatment precocity (how early) and duration of sustained virological response to highly active antiretroviral therapy (HAART) on HIV RNA levels after withdrawal of treatment started during primary infection and to compare HIV RNA levels after HAART withdrawal with levels reached at the same time point during the natural history of infection in the pre-HAART era. DESIGN: HIV RNA was analysed using linear mixed-effects models for 58 patients from the PRIMO cohort (1996-2003) treated during primary infection (with sustained virological responses until HAART interruption) and 116 untreated patients enrolled in the SEROCO cohort within 6 months following infection (1988-1995). Viral loads were estimated in PRIMO patients 36 months after infection (12 months after treatment interruption) and were estimated for the SEROCO patients 36 months after infection, after adjustment for gender and age. RESULTS: HIV RNA levels 12 months after HAART interruption were independently associated with levels at HAART initiation and with the CD4 cell count at HAART interruption, but not with the precocity of HAART or the duration of virological response to HAART. Thirty-six months after infection, mean HIV RNA levels were 3.95 log10 copies/ml 12 months after stopping HAART and 4.11 log10 copies/ml in never-treated patients. CONCLUSION: Viral load 12 months after withdrawal of transient effective HAART started during primary infection is similar to viral load at the same time after infection in never-treated patients, suggesting that early HAART initiation does not lower the virological set-point.

Early plasmacytoid dendritic cell changes predict plasma HIV load rebound during primary infection.

During human immunodeficiency virus (HIV) infection, interruption of highly active antiretroviral therapy (HAART) is usually followed by virus load rebound. Previous data have suggested a role for plasmacytoid dendritic cells (pDCs) in anti-HIV innate immunity. Here, the number of pDCs was measured by flow cytometry before, during, and after receipt of HAART in 7 patients with documented primary HIV-1 infection. A negative correlation was evidenced between pDC counts after 1 month of HAART and mean plasma virus load after interruption of HAART (r2=0.85; Spearman's partial rho =-0.92; P=.03). pDC counts during treatment might help predict immune replication control after interruption of HAART.

CD8+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection.

Primary viral infections, including primary HIV infection, trigger intense activation of the immune system, with marked expansion of CD38(+)CD8(+) T cells. Whether this expansion involves only viral-specific cells or includes a degree of bystander activation remains a matter of debate. We therefore examined the activation status of EBV-, CMV-, and influenza virus (FLU)-specific CD8(+) T cells during primary HIV infection, in comparison to HIV-specific CD8(+) T cells. The activation markers CD38 and HLA-DR were strongly expressed on HIV-specific CD8(+) T cells. Surprisingly, CD38 expression was also up-regulated on CD8(+) T cells specific for other viruses, albeit to a lesser extent. Activation marker expression returned to normal or near-normal values after 1 year of highly active antiretroviral therapy. HIV viral load correlated with CD38 expression on HIV-specific CD8(+) T cells but also on EBV-, CMV-, and FLU-specific CD8(+) T cells. In primary HIV infection, EBV-specific CD8(+) T cells also showed increased Ki67 expression and decreased Bcl-2 expression, compared with values observed in HIV-seronegative control subjects. These results show that bystander activation occurs during primary HIV infection, even though HIV-specific CD8(+) T cells express the highest level of activation. The role of this bystander activation in lymphocyte homeostasis and HIV pathogenesis remains to be determined.

Presence of HIV-specific CD4+ T-cell responses in HIV-infected subjects with sustained virologic control after highly active antiretroviral therapy.

HIV-specific CD4+ T-helper cell responses in 40 subjects with chronic infection (CI) who had virus suppression after highly active antiretroviral therapy (HAART) were compared with those in 34 subjects treated during primary infection (PI). A CD4+ T-cell proliferative response to HIV p24 protein was present in 50% of these subjects compared with 79% of subjects treated during PI. The existence of a proliferative response in CI subjects was associated with a higher CD4+ T-cell count at initiation of HAART, a longer duration of virus suppression, and a higher CD4+ T-cell count at the time of analysis. These results show that an HIV-specific proliferative response is preferentially observed in treated CI subjects with CD4+ T-cell counts of >200/microL. However, in treated CI subjects with a significant degree of CD4+ T-cell depletion (<200/microL), it may also be observed in 35% provided that the duration of virus suppression is long enough, which may have implications for future therapeutic strategies.

Impact of antiretroviral therapy and changes in virus load on human immunodeficiency virus (HIV)-specific T cell responses in primary HIV infection.

Human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T cell responses were evaluated prospectively in a large cohort of subjects with HIV primary infection via long-term follow-up examining different virological profiles related to different treatment interventions. No correlation was observed between baseline virus load and HIV-specific CD4(+) and CD8(+) T cell responses. Highly active antiretroviral therapy (HAART)-induced suppression of viremia was associated with an increase in CD4(+) T cell proliferative responses. The HIV-specific proliferative response also increased, at least in the first 18 months, in subjects with detectable viremia, either treated or untreated. The magnitude of the HIV-specific CD8(+) T cell response decreased with suppression of viremia. In subjects with detectable viremia, the breadth and magnitude of the HIV-specific CD8(+) T cell responses increased progressively. Finally, whether HAART was initiated before or after seroconversion had little effect on HIV-specific CD4(+) and CD8(+) T cell responses.