Terminal Differentiation of CD56 dim CD16 + Natural Killer Cells Is Associated with Increase in Natural Killer Cell Frequencies After Antiretroviral Treatment in HIV-1 Infection

Abstract

HIV-1 infection results in immunological abnormalities of natural killer (NK) cells such as disturbed distribution of NK cell subsets and downmodulation of activating and upregulation of inhibitory receptors thereby diminishing NK cell killing capacity and cytokine secretion. Antiretroviral treatment (ART) is known to restore phenotype and functions of NK cells. However, the effects of ART on NK cell terminal differentiation, activation, and disturbed distribution have not been studied yet longitudinally. Here, we analyzed the effects of ART on these parameters of peripheral blood NK cells in a longitudinal as well as in a cross-sectional study. We observed that expanded CD56⁻CD16⁺ NK cell frequency is inversely correlated with the frequency of CD56^dimCD16⁺ NK cells in treatment-naive HIV-1 patients. Loss of CD56^dimCD16⁺ and expansion of CD56⁻CD16⁺ NK cells again restore to the levels of healthy controls after ART. Enhanced immune activation of different NK cell subsets is partially restored after ART. Terminal differentiation of CD56^dimCD16⁺ NK cells is enhanced after ART as measured by CD57 expression. Frequencies of CD57⁺CD56^dimCD16⁺ NK cells are directly correlated with the frequencies of total NK cells suggesting that an increase in the frequencies of CD57⁺CD56^dimCD16⁺ NK cells is reflected by increased frequencies of total NK cells after ART. Taken together these data demonstrate that ART has an effect on the immune restoration of NK cells and is enhanced in the terminal differentiation of CD56^dimCD16⁺ NK cells, which is associated with increased frequencies of total NK cells after ART.