Phenotypic and functional characteristics of highly differentiated CD57+NKG2C+ NK cells in HIV-1-infected individuals

Natural killer (NK) cells are important anti-viral effector cells. The function and phenotype of the NK cells that constitute an individual's NK cell repertoire can be influenced by ongoing or previous viral infections. Indeed, infection with human cytomegalovirus (HCMV) drives the expansion of a highly differentiated NK cell population characterized by expression of CD57 and the activating NKG2C receptor. This NK cell population has also been noted to occur in HIV-1-infected individuals. We evaluated the NK cells of HIV-1-infected and HIV-1-uninfected individuals to determine the relative frequency of highly differentiated CD57+NKG2C+ NK cells and characterize these cells for their receptor expression and responsiveness to diverse stimuli. Highly differentiated CD57+NKG2C+ NK cells occurred at higher frequencies in HCMV-infected donors relative to HCMV-uninfected donors and were dramatically expanded in HIV-1/HCMV co-infected donors. The expanded CD57+NKG2C+ NK cell population in HIV-1-infected donors remained stable following antiretroviral therapy. CD57+NKG2C+ NK cells derived from HIV-1-infected individuals were robustly activated by antibody-dependent stimuli that contained anti-HIV-1 antibodies or therapeutic anti-CD20 antibody, and these NK cells mediated cytolysis through NKG2C. Lastly, CD57+NKG2C+ NK cells from HIV-1-infected donors were characterized by reduced expression of the inhibitory NKG2A receptor. The abundance of highly functional CD57+NKG2C+ NK cells in HIV-1-infected individuals raises the possibility that these NK cells could play a role in HIV-1 pathogenesis or serve as effector cells for therapeutic/cure strategies.