Persistence of Activated and Adaptive-Like NK Cells in HIV + Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy.

Innate immune dysfunction persists in HIV ⁺ individuals despite effective combination antiretroviral therapy (cART). We recently demonstrated that an adaptive-like CD56 ^dim NK cell population lacking the signal transducing protein FcRγ is expanded in HIV ⁺ individuals. Here, we analyzed a cohort of HIV ⁺ men who have sex with men (MSM, n  = 20) at baseline and following 6, 12, and 24 months of cART and compared them with uninfected MSM ( n  = 15) to investigate the impact of cART on NK cell dysfunction. Proportions of NK cells expressing markers of early (CD69 ⁺ ) and late (HLA-DR ⁺ /CD38 ⁺ ) activation were elevated in cART-naïve HIV ⁺ MSM ( p  = 0.004 and 0.015, respectively), as were FcRγ ^- NK cells ( p  = 0.003). Using latent growth curve modeling, we show that cART did not reduce levels of FcRγ ^- NK cells ( p  = 0.115) or activated HLA-DR ⁺ /CD38 ⁺ NK cells ( p  = 0.129) but did reduce T cell and monocyte activation ( p  < 0.001 for all). Proportions of FcRγ ^- NK cells were not associated with NK cell, T cell, or monocyte activation, suggesting different factors drive CD56 ^dim FcRγ ^- NK cell expansion and immune activation in HIV ⁺ individuals. While proportions of activated CD69 ⁺ NK cells declined significantly on cART ( p  = 0.003), the rate was significantly slower than the decline of T cell and monocyte activation, indicating a reduced potency of cART against NK cell activation. Our findings indicate that 2 years of suppressive cART have no impact on CD56 ^dim FcRγ ^- NK cell expansion and that NK cell activation persists after normalization of other immune parameters. This may have implications for the development of malignancies and co-morbidities in HIV ⁺ individuals on cART.