Distinct differentiation profiles of HIV-Gag and Nef-specific central memory CD8+ T cells associated with HLA-B57/5801 and virus control.

ABSTRACT

OBJECTIVES: A superior capacity of controlling HIV has been attributed to CD8(+) T cells directed against HIV-Gag compared to Nef, particularly in the context of some protective human leukocyte antigen (HLA) alleles. To further elucidate this protective effect, we compared the multifunctional and differentiation characteristics of CD8(+) T cells specific for HIV-Gag and Nef in HLA-B57/5801-positive and negative nonprogressors. METHODS: A head-to-head comparison of CD8(+) T cells specific for HIV-Gag and Nef frequencies, cytokine production and differentiation was conducted, in 11 HLA-B57/5801 and 11 HLA-B57/5801 HIV-infected individuals selected from a cohort of 53 nonprogressors by using IFN-gamma-ELISpot assay and flow cytometry analysis of intracellular cytokine production and differentiation profile. Correlations with HIV parameters were studied. RESULTS: Frequencies of Gag-specific but not of Nef-specific CD8(+) T cells correlated with peripheral blood mononuclear cell (PBMC)-associated HIV-DNA. The HIV-Gag and Nef-specific CD8(+) T cells did not differ for IL-2 production in either HLA-B57/5801 or HLA-B57/5801 individuals. The IFN-gamma-producing Gag-specific CD8(+) T cells in HLA-B57/5801 individuals significantly differed from their Nef-specific counterparts by displaying higher proportions of central memory CD45RACCR7 cells positive for CD27(+). This differentiation pattern was not observed in HLA-B57/5801 individuals. Only these HLA-B57/5801-positive Gag-specific CD27(+) central memory CD8(+) T cells, but not their Nef-specific counterparts, negatively correlated with cell-associated HIV-DNA. CONCLUSION: HLA-B57/5801 drives a preferential CD27(+) differentiation of central memory CD8(+) T cells directed against HIV-Gag but not Nef that may contribute to the ability of Gag-specific CD8(+) T cells to better control HIV in HLA-B57/5801 nonprogressors.