NK Count and Natural Cytotoxicity in Immune Nonresponders Versus Responders Living With HIV

Despite viral suppression with antiretroviral therapy, immune nonresponders (INR) among people living with HIV (PLWH) still have a higher risk of developing AIDS-related and non-AIDS-related complications. Our study aimed to investigate the phenotype and functions of Natural Killer (NK) cells in INR, to better understand underlying mechanisms of immune nonresponse. Our cross-sectional study included PLWH aged over 45 with an undetectable HIV viral load sustained for at least 2 years. Participant CD4⁺ T-cell counts exceeded 500 cells/mm³ for IR or below 350 cells/mm³ for INR. We characterized NK cell subsets, performed natural cytotoxicity and ADCC assays, and phenotyped NK cells before and after functional assays. Median CD4 levels were 247.5 (IQR, 208.8-286.3) cells/mm³ and 768.5 (IQR, 673.3-957.8) cells/mm³ in the INR (n = 20) and IR (n = 40), respectively. NK cell counts were lower in INR (p = 0.00066), but the percentages were similar between IR and INR. NKG2A was the only differentially expressed marker between groups, showing higher expression in INR. Additionally, NK cell natural cytotoxicity was elevated in the INR group. Multivariate analyses associated CD4 nadir and low NK cell count with immune nonresponse. Our results do not indicate a clear role for NK-mediated ADCC in immune nonresponse. We did not objectify an association between CD8 hyperactivation and INR.