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Background  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.    Materials and Methods  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.    Results  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.    Conclusions  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.

Potential Role for HIV-Specific CD38−/HLA-DR+ CD8+ T Cells in Viral Suppression and Cytotoxicity in HIV Controllers