Saez-Cirion, A. et al. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J. Immunol. 182, 7828-7837

Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 182(12):7828-37. DOI: 10.4049/jimmunol.0803928
Source: PubMed


"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.

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Available from: Asier Sáez-Cirión, Oct 08, 2015
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    • "Therefore in order to determine whether protective de novo responses were present in ES, we looked at the ability of CD8+ T cells to suppress replication of escape mutants. We used the suppression assay because Saez-Cirion and colleagues have demonstrated that the ability of unstimulated primary CD8+ T cells to inhibit viral replication correlates with elite control of HIV-1 infection [71,73], and we have recently confirmed this finding [72]. In a prior study, we demonstrated that CD8+ T cells from an HLA-B*57 ES suppressed multiple rare autologous TW10 escape variants by a non-cross reactive de novo response [74]. "
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    ABSTRACT: Elite Controllers or Suppressors (ES) are HIV-1 positive individuals who maintain plasma viral loads below the limit of detection of standard clinical assays without antiretroviral therapy. Multiple lines of evidence suggest that the control of viral replication in these patients is due to a strong and specific cytotoxic T lymphocyte (CTL) response. The ability of CD8+ T cells to control HIV-1 replication is believed to be impaired by the development of escape mutations. Surprisingly, viruses amplified from the plasma of ES have been shown to contain multiple escape mutations, and it is not clear how immunologic control is maintained in the face of virologic escape. We investigated the effect of escape mutations within HLA*B-57-restricted Gag epitopes on the CD8+ T cell mediated suppression of HIV-1 replication. Using site directed mutagenesis, we constructed six NL4-3 based viruses with canonical escape mutations in one to three HLA*B-57-restricted Gag epitopes. Interestingly, similar levels of CTL-mediated suppression of replication in autologous primary CD4+ T cells were observed for all of the escape mutants. Intracellular cytokine staining was performed in order to determine the mechanisms involved in the suppression of the escape variants. While low baseline CD8+ T cells responses to wild type and escape variant peptides were seen, stimulation of PBMC with either wild type or escape variant peptides resulted in increased IFN-gamma and perforin expression. These data presented demonstrate that CD8+ T cells from ES are capable of suppressing replication of virus harboring escape mutations in HLA-B*57-restricted Gag epitopes. Additionally, our data suggest that ES CD8+ T cells are capable of generating effective de novo responses to escape mutants.
    Retrovirology 12/2013; 10(1):152. DOI:10.1186/1742-4690-10-152 · 4.19 Impact Factor
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    • "We indeed found that EC with HLA-B57 or HLA-B27 had more effective CTL activity in our coculture assay and had lower reservoirs. This data is consistent with studies showing that effective Gag epitopes are important in controlling HIV [36,37]. Interestingly, this data is also consistent with our in vitro data that GPR cells can express Gag but not Env [21], as clearance by EC with effective Gag epitopes and greater Gag clearance had lower reservoirs. "
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    ABSTRACT: Resting CD4+T cells infected with HIV persist in the presence of suppressive anti-viral therapy (ART) and are barriers to a cure. One potential curative approach, therapeutic vaccination, is fueled by recognition of the ability of a subset of elite controllers (EC) to control virus without therapy due to robust anti-HIV immune responses. Controllers have low levels of integrated HIV DNA and low levels of replication competent virus, suggesting a small reservoir. As our recent data indicates some reservoir cells can produce HIV proteins (termed GPR cells for Gag-positive reservoir cells), we hypothesized that a fraction of HIV-expressing resting CD4+T cells could be efficiently targeted and cleared in individuals who control HIV via anti-HIV cytotoxic T lymphocytes (CTL). To test this we examined if superinfected resting CD4+T cells from EC express HIV Gag without producing infectious virus and the susceptibility of these cells to CTL. We found that resting CD4+T cells expressed HIV Gag and were cleared by autologous CD8+T cells from EC. Importantly, we found the extent of CTL clearance in our in vitro assay correlates with in vivo reservoir size and that a population of Gag expressing resting CD4+T cells exists in vivo in patients well controlled on therapy.
    PLoS ONE 08/2013; 8(8):e71879. DOI:10.1371/journal.pone.0071879 · 3.23 Impact Factor
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    • "Thus, spinoculation is resulting in a high level of interaction between virion and target cells that is CD4 and co-receptor specific, and largely requires fusion of the bound virion. To determine if the ES CD8+ T cell response to non-productively infected CD4+ T cells is superior to the response of CP CD8+ T cells, a variant of the CD8+ T cell suppression assay was used [21,22,41]. Freshly isolated, unstimulated CD4+ T cells were infected with 1000 ng of NL4-3 ΔEnv/GFP per 106 cells with or without treatment with 10 μM EFV, and co-cultured with either Gag-stimulated or unstimulated CD8+ T cells at E:T ratios ranging from 1:1 to 1:8. "
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    ABSTRACT: Elite controllers or suppressors have the remarkable capacity to maintain HIV-1 plasma RNA levels below the limit of detection of clinical assays (<50 copies/mL) without therapy and have a lower frequency of latently infected cells compared to chronic progressors. While it is unclear how this reduced seeding of the reservoir is achieved, it is possible that effective CTL responses play an in important role in limiting the size of the latent reservoir. Herein, we demonstrate that primary CD8+ T cells from HLA-B*57/5801 elite suppressors were able to efficiently eliminate resting and activated primary CD4+ T cells shortly after viral entry and prior to productive infection. CD8+ T cells from elite suppressors were significantly more effective at eliminating these cells than CD8+ T cells from chronic progressors. Nonproductively infected CD4+ T cells may represent a subpopulation of cells that are precursors to latently infected cells; therefore, the effective elimination of these cells may partially explain why elite suppressors have a much lower frequency of latently infected cells compared to chronic progressors. Thus, a vaccine strategy that elicits early and potent CD8+ T cell responses may have the capacity to limit the seeding of the latent reservoir in HIV-1 infection.
    Retrovirology 07/2013; 10(1):68. DOI:10.1186/1742-4690-10-68 · 4.19 Impact Factor
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