Activated NK Cells with Pro-inflammatory Features are Associated with Atherogenesis in Perinatally HIV-Acquired Adolescents.

Human immunodeficiency virus (HIV) is associated with persistent immune activation and dysfunction in people with HIV despite treatment with antiretroviral therapy (ART). Modulation of the immune system may be driven by: low-level HIV replication, co-pathogens, gut dysbiosis /translocation, altered lipid profiles, and ART toxicities. In addition, perinatally acquired HIV (PHIV) and lifelong ART may alter the development and function of the immune system. Our preliminary data and published literature suggest reprogramming innate immune cells may accelerate aging and increase the risk for future end-organ complications, including cardiovascular disease (CVD). The exact mechanisms, however, are currently unknown. Natural killer (NK) cells are a highly heterogeneous cell population with divergent functions. They play a critical role in HIV transmission and disease progression in adults. Recent studies suggest the important role of NK cells in CVDs; however, little is known about NK cells and their role in HIV-associated cardiovascular risk in PHIV adolescents. Here, we investigated NK cell subsets and their potential role in atherogenesis in PHIV adolescents compared to HIV-negative adolescents in Uganda. Our data suggest, for the first time, that activated NK subsets in PHIV adolescents may contribute to atherogenesis by promoting plasma oxidized low-density lipoprotein (Ox-LDL) uptake by vascular macrophages.

Synergistic Role of NK Cells and Monocytes in Promoting Atherogenesis in Severe COVID-19 Patients.

Clinical data demonstrate an increased predisposition to cardiovascular disease (CVD) following severe COVID-19 infection. This may be driven by a dysregulated immune response associated with severe disease. Monocytes and vascular tissue resident macrophages play a critical role in atherosclerosis, the main pathology leading to ischemic CVD. Natural killer (NK) cells are a heterogenous group of cells that are critical during viral pathogenesis and are known to be dysregulated during severe COVID-19 infection. Their role in atherosclerotic cardiovascular disease has recently been described. However, the contribution of their altered phenotypes to atherogenesis following severe COVID-19 infection is unknown. We demonstrate for the first time that during and after severe COVID-19, circulating proinflammatory monocytes and activated NK cells act synergistically to increase uptake of oxidized low-density lipoprotein (Ox-LDL) into vascular tissue with subsequent foam cell generation leading to atherogenesis despite recovery from acute infection. Our data provide new insights, revealing the roles of monocytes/macrophages, and NK cells in COVID-19-related atherogenesis.