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

Abstract

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 suppression ͉ CD8 ϩ T cells ͉ HLA-DR ͉ CD38

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

“…Second, none of the patients expressed a protective HLA (either B27 or B57 haplotype). Altogether, these results strongly suggest that vaccination with lipopeptide-pulsed GM-CSF/IFN-α DCs improved the quality of HIV-specific immune responses, which is associated with a lower viral rebound that is independent of the size of the viral reservoir.Of interest, some characteristics of the vaccine immune responses observed in our patients are reminiscent of those observed in elite controllers-an increase of polyfunctional CD4 + T cells that produce IL-2 and IFN-γ [12,13]. Moreover, the data also indicate that IL-13-and IL-21-secreting HIV-specific T cells before ATI are associated with a lower viral replication following ATI, an immunological feature described in elite controllers [14,15].…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Despite the low levels of circulating virus in HICs, high frequencies of HIV-specific CD8þ T cells have been observed in these individuals [67,120]. These cells have maintained their capacities to proliferate in the presence of HIV antigens and to secrete IL-2 and other cytokines and chemokines [121,122].…”

“…These cells have maintained their capacities to proliferate in the presence of HIV antigens and to secrete IL-2 and other cytokines and chemokines [121,122]. Moreover, HIV-specific CD8þ T cells in HICs have been reported to possess or rapidly upregulate cytotoxic granule contents [123,124], and accordingly have a striking capacity to eliminate infected autologous CD4þ T cells [67]. This enhanced capacity to suppress HIV infection is linked to a higher frequency of further differentiated cells in association with a discordant CD38 low HLA-DR high phenotype [67].…”

“…The HLA-B alleles B*27 and B*57, which are commonly overrepresented in HICs [65][66][67], are members of the Bw4-80I group [68], suggesting that NK cells may contribute to establishing HIV control in these patients through direct cytolytic or non-cytolytic anti-HIV activities or by favouring the induction of an efficient CD8þ T cell response (see below) through optimal crosstalk with dendritic cells. Various reports suggest that NK cells from HICs have increased cytolytic and secretory potential [69][70][71], which may be associated with particular NK cell receptor profiles [69,71].…”

“…Moreover, HIV-specific CD8þ T cells in HICs have been reported to possess or rapidly upregulate cytotoxic granule contents [123,124], and accordingly have a striking capacity to eliminate infected autologous CD4þ T cells [67]. This enhanced capacity to suppress HIV infection is linked to a higher frequency of further differentiated cells in association with a discordant CD38 low HLA-DR high phenotype [67]. HIV-specific CD8þ T cell responses in HICs preferentially target epitopes in Gag, and Gag-specific responses account for most of their capacity to suppress HIV infection [125], which may be due to faster recognition of infected cells [126].…”