Background:  HIV controllers (HIC) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This viral control is usually associated to strong functional HIV-specific CD8 T cell responses. Accordingly, we have recently shown that CD8 T cells from HIC strongly suppress ex vivo HIV-1 infection of autologous CD4 T cells, suggesting a crucial role of this response in vivo. Here we analyzed the relationship between this anti-HIV activity and the specific CD8 T cell responses in a larger group of HIC.

Methods:  We studied 20 patients infected with HIV-1 for more than 10 years who had never received antiretroviral treatment, and more than 90% of whose plasma HIV RNA measures fell below 400 copies/mL. Isolation of infecting viruses was attempted from phytohemagglutinin-interleukin-2 (PHA-IL-2) -activated CD4 T cells. HIV-specific CD8 T cell responses were measured by interferon-g (IFN-g) ELISpot, using optimal cytotoxic T lymphocyte (CTL) peptides derived from the HIV-1 Env, Gag, Pol, and Nef proteins, according to each patient HLA typing. CD8 T cell HIV suppressive capacity was evaluated by co-culture of unstimulated CD8 T cells with HIV-1_BaL-superinfected activated autologous CD4 T cells. HIV replication was evaluated either by p24 ELISA on supernatants or by fluorescence-activated cell forting (FACS) detection of intracellular p24. The rank sum test, linear regression analysis and Spearman’s rank correlation test were used for statistic analyses.

Results:  CD8 T cells from 14 of the 20 HIC showed strong HIV suppressive capacity ex vivo. This capacity was stable over time, was associated with HLA alleles B27 and B57, and was partially effective even on other primate lentiviruses. Notably, HIV-suppressive capacity of CD8 T cells correlated strongly with the frequency of Gag-specific CD8 T cells (Spearman 0.901, p <0.00001), but not with those of other specificities. We also identified 6 HIC who had weak HIV-suppressive CD8 T cell capacities and HIV-specific CD8 T cell responses. Among these 6 HIC, at least 3 had highly replicative viruses.

Conclusions:  Our results confirm that a strong CD8 T cell HIV-suppressive capacity is characteristic of most HIC, although the identification of weak-responder HIC suggests that host mechanisms unrelated to CD8 T cell response may also contribute to restrain HIV infection. Directly relevant to the development of effective T cell-based vaccines, our results underline the importance of Gag responses in the antiviral potency of CD8 T cells from strong-responder HIC.