Abstract Natural killer (NK) cells are critical modulators of HIV transmission and disease. While recent evidence suggests a loss of NK cell cytotoxicity during aging, a compound analysis of NK cell biology and aging in persons with HIV (PWH) is lacking. We set out to perform one of the first large comprehensive analyses of people aging with and without HIV to determine NK phenotypic changes during aging and how these changes are modulated while aging with HIV. Utilizing high-dimensional polychromatic flow cytometry we analyzed 30 immune-related proteins spanning broad functions such as trafficking, activation/inhibition, NK specific receptors, and memory/checkpoint receptors on peripheral NK cells from health donors, PWH with viral suppression, and viremic PWH. NK cell phenotypes are dynamic across the age span but are significantly altered in HIV and ART and with co-factors such as CMV. Specifically, NK cells in healthy aging show increasing levels of ⍰4β7 and decreasing CCR7 expression during aging, a phenomenon nearly perfectly reversed in PWH. These HIV-associated trafficking changes could be in part due to NK cell recruitment to HIV reservoir formation in lymphoid tissue or failed mucosal signaling in the HIV-infected gut, but regardless appear to be tight biomarkers of age-related NK cell changes.

Disruption of natural killer cell homing as a biomarker in persons aging with or without HIV