Antiretroviral therapy-induced dominant interleukin-2 HIV-1 Gag CD4+ T cell response: evidence of functional recovery of HIV-1-specific CD4+ T cells

Prolonged antiretroviral treatment (ART) significantly changes the cytokine secretion capacities of HIV-1-specific T cells. However, it is unclear whether these changes result from decreased viremia or they correspond to true functional recovery of viral-specific immune response. To study this issue, we analysed the quantitative and qualitative differences of HIV-1-specific and polyclonal CD4+ and CD8+ T cells between 26 naive and 52 treated individuals. HIV-1 Gag and staphylococcal enterotoxin B (SEB)-reactive T cells were determined by flowcytometric intracellular secretion of IFN-γ or/and ΙL-2. ART resulted in increase of single IL-2 and decrease of single IFN-γ-secreting HIV-1 CD4+ T cells, while both cytokines secreting HIV-1 CD4+ T cells were presented in comparable frequencies in both groups. Viral loads correlated negatively with single IL-2 and positively with single IFN-γ-secreting HIV-1 CD4+ cells. Single IL-2 HIV-1 CD4+ T cells correlated positively with both cytokines secreting polyclonal CD8+ T cells. By qualitative analysis, a dominant IL-2 HIV-1 CD4+ T cell response (> 70% single IL-2) was identified only in ART suppressed patients, who also generated increased dual specific polyclonal CD8+ T cells. Polyfunctional HIV-1 CD4+ T cell responses were detected even in naive individuals with high viremia. In conclusion, the presence of dominant IL-2 HIV-1 CD4+ T cell response, associated with increased CD8+ T cells capable to produce IL-2, indicates that the recovery of HIV-1-specific CD4+ T cell functionality under ART is a feasible goal. Furthermore, polyfunctional HIV-1 CD4+ T cell responses seem not to be directly involved in viral replication control.     

Characterization of HIV-1 Gag-specific T cell responses in chronically infected Indian population

India is at the epicentre of the global HIV/AIDS epidemic in South-east Asia, predominated by subtype C infections. It is important to characterize HIV-1-specific T cell responses in this particular population with the aim of identifying protective correlates of immunity to control HIV-1 infection. In this study, we performed a comprehensive analysis of the breadth and magnitude of T cell responses directed at HIV-1 subtype C Gag, one of the most conserved HIV-1 proteins. The study population consisted of antiretroviral naive, chronic HIV-1 subtype C-infected individuals at various stages of infection. We used recent advanced techniques such as enzyme-linked immunospot (ELISPOT) assay and intracellular cytokine staining to quantify the total CD4(+) and CD8(+) T cell response to HIV-1 gag at single peptide level, regardless of HLA haplotype of the infected individual. The p24-Gag was identified as the most frequently recognized subunit protein with the greatest magnitude of CD4(+) and CD8(+) T cell responses. Stronger and broader CD8 T cell responses were recognized, contrasting with the weaker and narrower CD4 T cell responses with regard to Gag protein subunits. The magnitude of the HIV-specific interferon (IFN)-gamma responses was observed to be higher than the corresponding interleukin (IL)-2 response, indicating the persistence of antigenic load in chronically infected Indian population due to the probable dysfunction of HIV-specific, IFN-gamma-secreting CD8 T cells in absence of IL-2 help.     

Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction

In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)-specific CD4(+) T cells but not CD8(+) T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4(+) T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4(+) T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4(+) T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4(+) T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.     

Immunological analysis of treatment interruption after early highly active antiretroviral therapy

We longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). After treatment interruption (TI), some individuals could maintain a low plasma viral load (<15,000 copies/mL), whereas others could not (>50,000 copies/mL). Before HAART was initiated, plasma viral load was similar. After TI, the numbers of CD8(+) T cells increased more in individuals without viral control, whereas individuals maintaining a low viral load showed a more pronounced increase in HIV-specific CD8(+) T-cell numbers. No differences were seen in the number or percentage of cytokine-producing HIV-1-specific CD4(+) T cells, or in proliferative capacity of T cells. Four weeks after TI, the magnitude of the total HIV-1-specific CD8(+) T-cell response (IFN-γ(+) and/or IL-2(+) and/or CD107a(+)) was significantly higher in individuals maintaining viral control. Degranulation contributed more to the overall CD8(+) T-cell response than cytokine production. Whether increased T-cell functionality is a cause or consequence of low viral load remains to be elucidated.     

CTL escape and increased viremia irrespective of HIV-specific CD4+ T-helper responses in two HIV-infected individuals

We investigated whether development of mutations leads to loss of CD8 T-cell recognition in HIV-1 infection and is possibly linked to alterations in HIV-1-specific CD4(+) T-cell responses in 2 HIV-infected individuals. In patient, H434 full genome sequencing of HIV-1 biological clones at early and late time points during disease progression showed development of fixed mutations in 16 predicted HIV-specific CTL epitopes. Loss of T-cell recognition and reactivity against wild-type and mutant epitopes was observed primarily for the HLA-B27-restricted KK10 epitope and HLA-A2-restricted SL9 epitope. Similarly, in patient H671, decreasing numbers of HLA-A3-restricted CD8(+) T cells specific for the wild-type RK9 epitope was observed after CTL escape. Only in patient H434 loss of CTL responses was paralleled by a decrease in HIV-specific IL-2(+) CD4(+) T-helper responses. This suggests that loss of T-cell reactivity may not be directly linked to HIV-specific CD4(+) T-cell responses but that increased viremia after CTL escape may influence CD4(+) T-helper responses.     

CD8 T-cell proliferative capacity is compromised in primary HIV-1 infection

Understanding the correlates of immunity that control HIV-1 infection is imperative to our understanding of HIV-1 disease and vaccine development. HIV-1-specific cytotoxic T lymphocytes are fundamental to the control of viremia; however, which T-cell repertoire components enact this control remains unclear. We hypothesize that polyfunctional HIV-1-specific CD8 T cells capable of viral control are present in most patients early in infection and these cells are distinguished by their ability to secrete interleukin (IL)-2 and proliferate. We examined HIV-1-specific CD8 T-cell proliferation and cytokine secretion in primary HIV-1 infection (PHI) using known HIV-1 cytotoxic T-cell epitopes to exclude CD4 bystander effect. We found that only a subset of patients with PHI demonstrated "CD4-independent" CD8 proliferation ex vivo. The remainder of the patients lacked HIV-1-specific CD8 T cells with proliferative capacity, even after the addition of exogenous IL-2. Among the proliferators, IL-2 production from the total HIV-specific CD8 T-cell population correlated with proliferation. Surprisingly, though, we did not routinely detect both IL-2 secretion and proliferative capacity from the same antigen-specific CD8 T cells. Thus, there are distinct and heterogeneous populations of CD8 T cells, phenotypically characterized by either proliferation or IL-2 secretion and few with dual capacity. Generation of these responses may be an important measure of HIV-1 control but are not universal after PHI. Furthermore, the heterogeneity of this population suggests that a simple measure of an effective vaccine response remains elusive.     

CD8+ T cell responses to human immunodeficiency viruses type 2 (HIV-2) and type 1 (HIV-1) gag proteins are distinguishable by magnitude and breadth but not cellular phenotype

The mechanisms underlying the relatively slow progression of human immunodeficiency virus type 2 (HIV-2) compared with HIV-1 infection are undefined and could be a result of more effective immune responses. We used HIV-2 and HIV-1 IFN-gamma enzyme-linked immunospot assays to evaluate CD8(+) T cell responses in antiretroviral-naive HIV-2- ('HIV-2(+)') and HIV-1-infected ('HIV-1(+)') individuals. Gag-specific responses were detected in the majority of HIV-2(+) and HIV-1(+) subjects. Overlapping gag peptide analysis indicated a significantly greater magnitude and breadth of responses in the HIV-1(+) cohort, and this difference was attributable to low responses in HIV-2(+) subjects with undetectable viral load (medians 2107 and 512 spot-forming units per 10(6) PBMC, respectively, p=0.007). We investigated the phenotype of viral epitope-specific CD8(+) T cells identified with HLA-B53- and HLA-B58-peptide tetramers (8 HIV-2(+), 11 HIV-1(+) subjects). HIV-2-specific CD8(+) T cells were predominantly CD27(+) CD45RA(-), and only a minority expressed perforin. The limited breadth and low frequency of CD8(+) T cell responses to HIV-2 gag in aviremic HIV-2(+) subjects suggests that these responses reflect antigen load in plasma, as is the case in HIV-1 infection. Immune control of HIV-2 does not appear to be related to the frequency of perforin-expressing virus-specific CD8(+) T cells.     

Immune Reconstitution and Viral Stimulation Are Required to Restore HIV-Specific CD8 T Cell Responses Following Advanced Infection

The extent to which highly active antiretroviral therapy (HAART) restores human immunodeficiency virus (HIV)-specific immunity in advanced infection is unknown. Therefore, we studied how effective therapy affected HIV-specific CD8(+) T cell responses in 4 individuals who had progressed to advanced infection. CD8(+) T cell responses were assessed by cytotoxicity and interferon-gamma (IFN-gamma) production. Proliferative CD4(+) T cell responses against HIV, Candida and mitogen were measured by (3)H-thymidine incorporation. Substantial immune reconstitution indicated by increased CD4(+) and CD8(+) T cell numbers followed suppression of viral replication. This was associated with emergence of HIV-specific cytotoxic T lymphocytes (CTL), but only concurrent with detectable viral replication. Emergent anti-HIV CTL were similar to those at earlier stages of infection in terms of their specificity, function, and CD28 phenotype. However, they were very short-lived in the absence of detectable HIV replication. Antigen-specific CD4(+) T cell responses remained severely compromised. Thus, effective antiretroviral therapy restores the capacity for HIV-specific CTL responses after advanced infection. However, the transient nature of these responses suggests failure to generate stable long-lived memory cells in the absence of HIV-specific helper T cell responses.     

Characterization of HIV-1-specific cytotoxic T lymphocytes expressing the mucosal lymphocyte integrin CD103 in rectal and duodenal lymphoid tissue of HIV-1-infected subjects

Acute HIV-1 infection depletes CD4(+) T cells in gut-associated lymphoid tissue (GALT). The failure of containment of local viral replication, and consequent CD4(+) T cell depletion, might be due to delayed mobilization of effector CD8(+) T cells or absence of functioning HIV-1-specific CD8(+) T cell effectors within GALT. No studies have addressed human intestinal HIV-1-specific CD8(+) T cell functions. We sought to determine whether functional HIV-1-specific CTL were present in GALT and whether the repertoire differed from HIV-1-specific CTL isolated from peripheral blood mononuclear cells. From three HIV-1-infected subjects, we isolated HIV-1-specific CD8(+) T cells expressing the mucosal lymphocyte integrin CD103 from GALT. These antigen-specific effector cells could be expanded in vitro and lysed target cells in an MHC class I-restricted manner. HIV-1-specific CTL could be isolated from both duodenal and rectal GALT sites, indicating that CD8(+) effectors were widespread through GALT tissue. The breadth and antigenic specificities of GALT CTL appeared to differ from those in peripheral blood in some cases. In summary, we found HIV-1-specific CD8(+) effector T cells in GALT, despite HIV-1-induced CD4(+) T cell lymphopenia. This suggests that HIV-1-specific CTL in gut tissue can be maintained with limited CD4(+) T cell help.     

Studies of HIV-associated immune responses in lymphoid compartments

Acute HIV-1 infection results in profound depletion of CD4+ memory T cells in lymphoid tissue (LT) and subsequent persistent replication in activated CD4+ T cells despite induction of an HIV-specific cell-mediated immune response. Interferon-α, proinflammatory cytokines, and β-chemokine production is present in LT. However, impaired expression of co-stimulatory molecules including CD80, CD86, and CD40L may contribute to low polyfunctional CD4+ T cell as well CD8+ T-cell activity. Accumulation of regulatory CD4+ T cells in LT may add to the lack of HIV-specific CD4+ T-cell proliferation and dysfunctional cytotoxic CD8+ T-cell response in LT.     

Frequency and function of HIV-specific CD8(+) T cells

The virus-specific CD8(+) T cell responses of 27 HIV-infected patients were studied, including a unique cohort of long term nonprogressors (LTNP) with normal CD4(+) T cell counts, low levels of plasma viral RNA, strong proliferative responses to HIV antigens and an over-representation of the HLA B*5701 class I allele. The frequencies of CD8(+) T cells specific to the majority of HIV gene products were measured by flow cytometric detection of intracellular interferon-gamma (IFN-gamma) in response to HIV-vaccinia recombinant infected autologous B cells. Very high frequencies (1.4-22%) of circulating CD8(+) T cells were found to be HIV-specific and were not only found in LTNP with reduced plasma virus. No correlation was evident between the frequency of HIV-specific CD8(+) T cells and levels of plasma viremia. In each case, the vast majority of cells (up to 17.2%) responded to Gag-Pol gene products. Although similar frequencies of Gag peptide-specific CD8(+) T cells were found in LTNP and progressors by either intracellular IFN-gamma or MHC class I tetramer staining, the breadth of these responses was greater in patients with progressive HIV infection compared with the LTNP group. The frequency of CD8(+) T cells specific for a single peptide was not representative of an individual patient's total HIV-specific CD8(+) T cell response. These data demonstrate that high numbers of HIV-specific CD8(+) T cells exist even in patients with high level viremia and progressive disease. Further, they suggest that other qualitative parameters of the CD8(+) T cell response may differentiate some patients with very low levels of plasma virus and nonprogressive infection.     

HIV-Specific CD4(+) and CD8(+) immune responses are generated with a gp120-depleted, whole-killed HIV-1 immunogen with CpG immunostimulatory sequences of DNA.

We examined the adjuvant effects of a synthetic CpG oligodeoxynucleotide immunostimulatory sequence (ISS) using a whole-killed, gp120-depleted HIV antigen (HIV-1 antigen) in a Lewis rat model. We hypothesized that HIV-1-specific CD4(+) T helper (Th) immune responses could be enhanced when an ISS was combined with an HIV-1 antigen in incomplete Freund's adjuvant (IFA). We also reasoned that if such Th responses were sufficient, such a combination might also induce HIV-specific CD8(+) T cell immune responses. Here we demonstrate that the HIV-1 antigen in IFA combined with ISS stimulates both CD4(+) and CD8(+) HIV-specific immune responses as measured by interferon-gamma (IFN-gamma) in the ELISPOT assay. A strong correlation between these CD4(+) and CD8(+) responses was demonstrated. Furthermore, we found that the HIV-1 antigen in IFA with ISS as an adjuvant stimulated strong antibody responses to core antigen (p24). These studies suggest that the combination of the whole-killed, gp120-depleted HIV-1 antigen in IFA with ISS may be an ideal candidate to test in nonhuman primates and in human studies as a preventive HIV-1 vaccine.     

Functional restoration of human immunodeficiency virus and Epstein-Barr virus-specific CD8(+) T cells during highly active antiretroviral therapy is associated with an increase in CD4(+) T cells

To investigate the effect of highly active antiretroviral therapy (HAART) on HIV- and Epstein-Barr virus (EBV)-specific CD8(+) T cells, total number and function of these cells was determined in 16 HIV-infected individuals using tetrameric HLA-peptide complexes and IFN-gamma ELISPOT assays after peptide stimulation, respectively. HAART induced a significant decrease in HIV-specific tetramer(+) T cells, whereas EBV-specific tetramer(+) T cells did not change. In addition, individuals who temporarily failed on therapy showed a temporary increase in the number of HIV-specific T cells, suggesting that differences in the pool size of antigen-specific T cells was determined by the presence of antigen. Interestingly, there was an increase in the ratio of IFN-gamma-producing T cells per total number of both HIV- and EBV-specific T cells in the majority of individuals, suggesting that the function of virus-specific T cells is improved in individuals successfully treated with HAART. Despite this relative functional improvement of EBV-specific T cells, no significant changes were observed in EBV load. In four subjects who temporarily failed on HAART, the percentage of IFN-gamma-producing T cells, both for HIV and EBV, paralleled CD4(+) T cell kinetics, suggesting that function seems to be related to differences in CD4(+) T cell numbers. Overall, these data indicate that HAART improves the antigen responsiveness of both HIV- and EBV-specific T cells, which is associated with an increase in CD4(+) T cells.     

Maturation of dendritic cells for enhanced activation of anti-HIV-1 CD8(+) T cell immunity

Maturation of dendritic cells (DC) to enhance their capacity to activate T cell immunity to HIV-1 is a key step in immunotherapy of HIV-1 infection with DC. We compared maturation of DC derived from HIV-1-uninfected subjects and infected subjects on antiretroviral therapy (ART) or ART na?ve by CD40 ligand (CD40L) and combinations of TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] and inflammatory cytokines IFN-gamma, IFN-alpha, IL-1beta, and TNF-alpha. The greatest levels of virus-specific IFN-gamma production by CD8(+) T cells were stimulated by DC treated with CD40L, followed by DC treated with the poly(I:C)-cytokine combination. The highest levels of IL-12p70 were produced by DC treated with CD40L + IFN-gamma, followed by CD40L and the poly(I:C)-cytokine combination. Neutralization of IL-12p70 indicated that it was only partially involved in direct enhancement of antiviral CD8(+) T cell activity. DC stimulation of antiviral CD8(+) T cell reactivity was enhanced by activated CD4(+) T cells at low concentrations but was suppressed at higher CD4(+) T cell concentrations. Maturation of DC with CD40L obviated the need for CD4(+) T cell help and overcame this suppressive activity. Finally, we showed that DC from HIV-1-infected subjects on ART, which were treated with the poly(I:C)-cytokine combination, retained the capacity to produce IL-12p70 and activate anti-HIV-1 CD8(+) T cell responses after restimulation with CD40L, with or without IFN-gamma. Thus, DC from HIV-1-infected subjects can be engineered with CD40L or a poly(I:C)-cytokine combination for enhancing CD8(+) T cell responses to HIV-1, which has potential applications in HIV-1 immunotherapy.     

Highly dampened HIV-specific cytolytic effector T cell responses define viremic non-progression

This study reports on HIV-specific T cell responses in HIV-1 infected Viremic Non-Progressors (VNPs), a rare group of people living with HIV that exhibit asymptomatic infection over several years accompanied by stable CD4+ T cell counts in spite of ongoing viral replication. We attempted to identify key virus-specific functional attributes that could underlie the apparently paradoxical virus-host equilibrium observed in VNPs. Our results revealed modulation of HIV-specific CD4+ and CD8+ effector T cell responses in VNPs towards a dominant non-cytolytic profile with concomitantly diminished degranulation (CD107a+) ability. Further, the HIV specific CD8+ effector T cell response was primarily enriched for MIP-1β producing cells. As expected, concordant with better viral suppression, VCs exhibit a robust cytolytic T cell response. Interestingly, PuPs shared features common to both these responses but did not exhibit a CD4+ central memory IFN-γ producing Gag-specific response that was shared by both non-progressor (VC and VNP) groups, suggesting CD4 helper response is critical for non-progression. Our study also revealed that cytolytic response in VNPs is primarily limited to polyfunctional cells while both monofunctional and polyfunctional cells significantly contribute to cytolytic responses in VCs. To further understand mechanisms underlying the unique HIV-specific effector T cell response described here in VNPs we also evaluated and demonstrated a possible role for altered gut homing in these individuals. Our findings inform immunotherapeutic interventions to achieve functional cures in the context of ART resistance and serious non AIDS events.     

Comprehensive analyses of a unique HIV-1-infected nonprogressor reveal a complex association of immunobiological mechanisms in the context of replication-incompetent infection

We recently demonstrated that a unique HIV-1-infected nonprogressor was infected with a nonevolving replication-incompetent HIV-1 strain, showing a total absence of viral evolution in vivo. Potent immune responses against HIV-1 were observed in his PBMC, despite an apparent lack of viral replication for at least 8 years. His PBMC resisted superinfection with CCR5, CXCR4, and dual-tropic HIV-1 strains, although highly purified CD4+ T cells supported infection, but without any visible cytopathic effect. Potent noncytolytic CD8+ T cell antiviral activity was shown to protect his PBMC from productive infection. This activity was not mediated by several known chemokines or IFN-gamma, which were produced at high levels after PHA activation of his CD8+ T cells, indicating the action of other CAF-like CD8 factors. This antiviral activity was a memory response, induced by HIV-specific stimulation to similar levels observed by PHA stimulation, but absent in ex vivo resting T cells. Immunological mechanisms associated with this antiviral suppressive activity included vigorous Gag-specific helper T cell proliferative responses and high-level IFN-gamma release by both CD4 and CD8 T cells. These responses were broadly directed against multiple Gag epitopes, both previously reported and some novel epitopes. Strong HIV-specific helper T cell function was also associated with strong neutralizing antibodies. Understanding how to induce these protective immune responses in other individuals could provide a major step forward in the design of effective immunotherapies or vaccines against HIV infection.     

Progressive loss of IL-2-expandable HIV-1-specific cytotoxic T lymphocytes during asymptomatic HIV infection

In HIV-1 infection, circulating HIV-1-specific cytotoxic T lymphocytes (CTL) exist in different states of activation, including activated cytotoxic cells and memory cells. We report that a subpopulation of HIV-1-specific CTL is capable of clonal expansion upon culture with IL-2 without exogenous antigen. The IL-2-expandable HIV-1-specific CTL precursor frequency was reduced in patients with advancing infection, although HIV-1-specific memory CTL could still be detected by stimulation in vitro with allele-specific HIV-1 peptide. Longitudinal analysis during advancing infection showed a progressive decline in the IL-2-expandable HIV-1-specific CTL precursor (CTLp) frequency without a decline in Epstein-Barr virus (EBV)-specific or allo-specific CTLp frequencies. To address mechanisms that may contribute to the decline in the IL-2-expandable HIV-specific CTL response, the requirements for in vitro generation of HIV-1-specific and EBV-specific effector CTL were examined. In the absence of exogenous IL-2 in limiting dilution, generation of EBV-specific CD8⁺ effector CTL was dependent upon help from CD4⁺ cells. CD4⁺ help for EBV-specific CD8⁺ CTL was observed in asymptomatic HIV infection but not in advanced infection. In the presence of exogenous IL-2, CD4⁺ cells could also provide help for the optimal generation of HIV-1 peptide-specific CD8⁺ CTL, because in vitro depletion of CD4⁺ cells prior to culture using stimulation with an MHC class I-restricted HIV-1 peptide reduced the peptide-specific CD8⁺ CTL response. We conclude that there is a decline in the IL-2-expandable HIV-1-specific CTL response during advancing infection. There are a number of possible mechanisms for this decline, including a reduction in CD4⁺ T cell help for in vivo antigen-activated CD8⁺ T cells.     

CD8+ T cells from most HIV-1-infected patients, even when challenged with mature dendritic cells, lack functional recall memory to HIV gag but not other viruses

Chronically HIV-1-infected patients fail to contain their viremia despite high frequencies of HIV-1-specific, IFN-gamma-producing CD8(+) T cells. However, these cells are known to exhibit both phenotypic and functional defects. We tested if mature dendritic cells (DC) could correct defective HIV-1 gag-specific T cell responses and if responses to other viral antigens were comparably affected. The circulating gag-specific CD8(+) T cells in fresh blood reliably produced IFN-gamma but lacked IL-2 and high perforin levels and failed to expand significantly during culture with mature DC presenting HIV-1 gag peptides. In contrast, CD8(+) T cells from long-term nonprogressors contained gag-specific IFN-gamma and IL-2 double producers, and the numbers of IFN-gamma producers expanded approximately 15-fold during culture with DC. DC from chronically infected patients could expand IFN-gamma- and IL-2-producing cells specific for influenza, cytomegalovirus and Epstein Barr virus, and the expansions were comparable to those in healthy donors. When the proliferative capacity of CD8(+) T cells from progressor patients was assessed by CFSE dilution, proliferation to other viral antigens was more vigorous than to HIV-1 gag. Therefore, monocyte-derived DC from HIV patients present viral antigens effectively, but there is a selective inability to expand CD8(+) IFN-gamma-producing and IFN-gamma and IL-2 double-producing T cells when challenged with HIV-1 gag.     

Immune responses and reconstitution in HIV-1 infected individuals: impact of anti-retroviral therapy, cytokines and therapeutic vaccination

Most patients with chronic HIV-1 infection lack functional CD4(+) and CD8(+) HIV-1-specific T cells with proliferative and cytolytic capacity, respectively. This is despite being able to produce intracellular cytokines in response to viral antigens. Protease inhibitor (PI)-based highly active anti-retroviral therapy (HAART) is unable to completely eradicate virus and fails to enable total restoration of immunity including induction of anti-HIV-1 responses. We have taken novel approaches towards the treatment of chronic HIV-1 disease with the aim of instigating long-term non-progressor status and depletion of virus reservoirs. HIV-1-specific CD4(+) and CD8(+) T cell responses were measured following the administration of cytokines, during therapeutic vaccination, and following treatment interruption (TI) or drug therapy change. Administration of cytokines, with or without therapeutic vaccination, in HAART treated patients, improved both CD4(+) and CD8(+) HIV-1-specific T cell responses even in late-stage disease. Virus-specific T cell responses were also seen during TI or when transient viraemia was apparent, and following therapy change from a PI- to a non-nucleoside-based HAART regimen. Reconstitution of HIV-1-specific immune responses was found to be transient and reversal to the previous anergic state was rapid. Viral reservoirs in the latently infected resting CD4(+) T cells, on follicular dendritic cells of germinal centers or even in infected thymic epithelium may be involved in clonal suppression and anergy. These may present major obstacles to the maintenance of HIV-1-specific responses and the eventual eradication of HIV-1.