Heterogeneity in HIV Suppression by CD8 T Cells from HIV Controllers: Association with Gag-Specific CD8 T Cell Responses

Abstract

“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.

Rapid, efficient functional characterization and recovery of HIV-specific human CD8 + T cells using microengraving

“…More complex functions, such as proliferation or simultaneous expression of multiple cytokines, may better identify effective CD8 + cytotoxic T lymphocytes (36,37). The ability of CTLs to recognize and kill virus-infected cells may be critical for mediating control in vivo, and it may be crucial to evaluate these functions comprehensively in vitro (38). We show that functional characterization of individual clones by in vitro viral-inhibition assays can identify functionality linked to single epitopes not detected by similar bulk assays.…”

Elite Controllers and Long-term Nonprogressors: Models for HIV Vaccine Development?

“…CD8 cells also demonstrate antiviral effects by inhibiting virus production from super-infected CD4 cells in elite controllers [36,38]. The intense cell-mediated response to HIV infection has not been demonstrated in all elite controllers suggesting that other viral control mechanisms are in effect [9,40]. Other possible mechanisms may include innate immunity mediated by natural killer cells, as evidenced by the strong association of KIR3DL1 allele in HLA B57 positive individuals [41][42][43].…”

CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

“…These individuals, termed elite controllers, have moved into the center of current efforts to identify correlates of immune protection against HIV-1, but the mechanisms responsible for undetectable HIV-1 viremia in these patients remain unresolved. HIV-1-specific CD8 + T cells from elite controllers have specific cytotoxic (3), proliferative (4,5), and cytokine secretion (6) properties and are effective in restricting HIV-1 replication in in vitro tissue culture experiments (7,8), but they are not a sufficient, and sometimes not even a necessary, component of effective immune activity against HIV-1 in vivo (9). Although the major genetic determinants of HIV-1 control have recently been shown to relate to specific amino acid polymorphisms in the HLA-B binding cleft (10), these account for less than 25% of the variability in viral load (VL), further suggesting that mechanisms other than T cell-mediated immune activity play a role in HIV-1 immune defense in elite controllers.…”