AUTHOR=Hearps Anna C. , Agius Paul A. , Zhou Jingling , Brunt Samantha , Chachage Mkunde , Angelovich Thomas A. , Cameron Paul U. , Giles Michelle , Price Patricia , Elliott Julian , Jaworowski Anthony TITLE=Persistence of Activated and Adaptive-Like NK Cells in HIV+ Individuals despite 2 Years of Suppressive Combination Antiretroviral Therapy JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2017 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00731 DOI=10.3389/fimmu.2017.00731 ISSN=1664-3224 ABSTRACT=

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.