High Frequencies of Polyfunctional CD8 + NK Cells in Chronic HIV-1 Infection Are Associated with Slower Disease Progression

Abstract

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.