Abstract
Innate immune dysfunction persists in HIV+ individuals despite effective combination antiretroviral therapy (cART). We recently demonstrated that an adaptive-like CD56dim 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 CD56dim 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 CD56dim 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.
Highlights
Effective combination antiretroviral therapy suppresses HIV replication and prevents AIDS-related illness but does not eliminate HIV or fully restore immune function
The HIV epidemic is concentrated in at-risk populations such as men who have sex with men (MSM), yet demographic and clinical differences that exist between these populations and the general community [i.e., prevalence of smoking, sexually transmitted infections, human CMV (HCMV) seropositivity (34)] are rarely considered in immunological studies
MSM had higher levels of IgG antibodies reactive with the HCMV envelope protein glycoprotein B (gB) (Figure 1A, p = 0.047) and showed significantly increased proportions of FcRγ− NK cells
Summary
Effective combination antiretroviral therapy (cART) suppresses HIV replication and prevents AIDS-related illness but does not eliminate HIV or fully restore immune function. Our cross-sectional study demonstrated increased NK cell activation and heightened spontaneous degranulation in both viremic and virologically suppressed HIV+ individuals (2), indicating NK cell activation persists despite effective cART. Recent studies associate HCMV infection with expansion of multiple subsets of adaptive-like NK cells, including (but not limited to) those expressing NKG2C (20–22) These “imprinted” populations are stably maintained for at least 15 months following infection (23) and show enhanced antibody-dependent activation (21), consistent with an important role in protective immunity against viral infections. An analogous population of CD56dimFcRγ− NK cells has previously been characterized in HIV−/HCMV+ individuals and shown to possess a memory-like phenotype with adaptive immune features including enhanced ADCC against target cells infected with HCMV or herpes simplex virus, implying a specialized role in antibody-dependent cross-protection (22, 32). We used latent growth curve modeling to quantify the rate at which NK cell activation is reversed following viral suppression as compared to activation of other immune cell compartments
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