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Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

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.

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. 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. 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. 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.

HIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors. In contrast MDDCs from HICs are particularly efficient at capturing HIV-1 particles when compared to cells from healthy donors or HIV-1 patients with suppressed viral load on antiretroviral treatment. MDDCs from HICs expressed on their surface high levels of syndecan-3, DC-SIGN and MMR, which could cooperate to facilitate HIV-1 capture. The combination of low susceptibility to HIV-1 infection but enhanced capacity to capture particles might allow MDDCs from HICs to preserve their function from the deleterious effect of infection while facilitating induction of HIV-specific CD8+ T cells by cross-presentation in a context of low viremia.

The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time. Despite high frequencies of polyfunctional HIV-specific CD8+ T-cells and a strong CD4+ T-helper response, CD8+ T-cells from 48 patients lacked strong HIV-suppressive capacities ex vivo. This indicates that the superior HIV-suppressive capacity of CD8+ T-cells from HIV controllers is not a general characteristic of the HIV-specific CD8+ T cell response in primary HIV infection.

To advance T cell–based HIV vaccine development, it is necessary to evaluate the immune correlates of a protective CD8 + T-cell response. We have developed an assay that assesses the capacity ex vivo of HIV-specific CD8 + T cells to suppress HIV-1 infection of autologous CD4 + T cells. This assay directly reflects the ultimate effector function of CD8 + T cells, the elimination of infected cells, and accurately differentiates the effective CD8 + T-cell response in spontaneous HIV controllers from ineffective responses in other patients. In this article, we describe all the steps from cell purification to assessment of viral replication by HIV-p24 ELISA and analysis, along with conditions for cell culturing, and how to choose the viral infectious dose that gives the most reliable results. We also depict the conditions of a rapid assay on the basis of flow cytometry analysis of intracellular HIV-Gag products. These procedures take 14–17 d when the p24 ELISA assay is used, or 6 d with the intracellular Gag assay.

HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38.sup.- /HLA-DR.sup.+ HIV-specific CD8.sup.+ T cells. Here we examined the role of this subset in HIC status. We compared CD38.sup.- /HLA-DR.sup.+ CD8.sup.+ T cells with the classical CD38.sup.+ /HLA-DR.sup.+ 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-[gamma] and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated. Compared to CD38.sup.+ /HLA-DR.sup.+ cells, CD38.sup.- /HLA-DR.sup.+ 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.sup.- /HLA-DR.sup.+ profile was preferentially generated in response to low viral antigen concentrations. These data highlight the role of CD38.sup.- /HLA-DR.sup.+ HIV-specific CD8.sup.+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8.sup.+ subset may be important for vaccine strategies.

To advance T cell-based HIV vaccine development, it is necessary to evaluate the immune correlates of a protective CD8 super(+) T-cell response. We have developed an assay that assesses the capacity ex vivo of HIV-specific CD8 super(+) T cells to suppress HIV-1 infection of autologous CD4 super(+) T cells. This assay directly reflects the ultimate effector function of CD8 super(+) T cells, the elimination of infected cells, and accurately differentiates the effective CD8 super(+) T-cell response in spontaneous HIV controllers from ineffective responses in other patients. In this article, we describe all the steps from cell purification to assessment of viral replication by HIV-p24 ELISA and analysis, along with conditions for cell culturing, and how to choose the viral infectious dose that gives the most reliable results. We also depict the conditions of a rapid assay on the basis of flow cytometry analysis of intracellular HIV-Gag products. These procedures take 14-17 d when the p24 ELISA assay is used, or 6 d with the intracellular Gag assay.

To advance T cell-based HIV vaccine development, it is necessary to evaluate the immune correlates of a protective CD8.sup.+ T-cell response. We have developed an assay that assesses the capacity ex vivo of HIV-specific CD8.sup.+ T cells to suppress HIV-1 infection of autologous CD4.sup.+ T cells. This assay directly reflects the ultimate effector function of CD8.sup.+ T cells, the elimination of infected cells, and accurately differentiates the effective CD8.sup.+ T-cell response in spontaneous HIV controllers from ineffective responses in other patients. In this article, we describe all the steps from cell purification to assessment of viral replication by HIV-p24 ELISA and analysis, along with conditions for cell culturing, and how to choose the viral infectious dose that gives the most reliable results. We also depict the conditions of a rapid assay on the basis of flow cytometry analysis of intracellular HIV-Gag products. These procedures take 14-17 d when the p24 ELISA assay is used, or 6 d with the intracellular Gag assay.

To advance T cell-based HIV vaccine development, it is necessary to evaluate the immune correlates of a protective [CD8.sup.+] T-cell response. We have developed an assay that assesses the capacity ex vivo of HIV-specific [CD8.sup.+] T cells to suppress HIV-1 infection of autologous [CD4.sup.+] T cells. This assay directly reflects the ultimate effector function of [CD8.sup.+] T cells, the elimination of infected cells, and accurately differentiates the effective [CD8.sup.+] T-cell response in spontaneous HIV controllers from ineffective responses in other patients. In this article, we describe all the steps from cell purification to assessment of viral replication by HIV- p24 ELIsA and analysis, along with conditions for cell culturing, and how to choose the viral infectious dose that gives the most reliable results. We also depict the conditions of a rapid assay on the basis of flow cytometry analysis of intracellular HIV-Gag products. These procedures take 14-17 d when the p24 ELISA assay is used, or 6 d with the intracellular Gag assay.