Natural killer (NK) cells are effector and regulatory innate immune cells and play a critical role in the first line of defense against various viral infections. Although previous reports have indicated the vital contributions of NK cells to HIV-1 immune control, nongenetic NK cell parameters directly associated with slower disease progression have not been defined yet. In a longitudinal, retrospective study of 117 untreated HIV-infected subjects, we show that higher frequencies as well as the absolute numbers of CD8⁺ CD3⁻ lymphocytes are linked to delayed HIV-1 disease progression. We show that the majority of these cells are well-described blood NK cells. In a subsequent cross-sectional study, we demonstrate a significant loss of CD8⁺ NK cells in untreated HIV-infected individuals, which correlated with HIV loads and inversely correlated with CD4⁺ T cell counts. CD8⁺ NK cells had modestly higher frequencies of CD57-expressing cells than CD8⁻ cells, but CD8⁺ and CD8⁻ NK cells showed no differences in the expression of a number of activating and inhibiting NK cell receptors. However, CD8⁺ NK cells exhibited a more functional profile, as detected by cytokine production and degranulation.

IMPORTANCE We demonstrate that the frequency of highly functional CD8⁺ NK cells is inversely associated with HIV-related disease markers and linked with delayed disease progression. These results thus indicate that CD8⁺ NK cells represent a novel NK cell-derived, innate immune correlate with an improved clinical outcome in HIV infection.