NK Cell Dysregulation May Potentiate Cardiovascular Disease in Adolescents with Perinatally Acquired HIV on Antiretroviral Therapy

Perinatally acquired HIV (PHIV) and antiretroviral therapy (ART) can alter innate immune cells, (monocytes and natural killer [NK] cells) which are important in the pathogenesis of cardiovascular disease (CVD). We compared cardiovascular biomarkers and immune signatures between PHIV adolescents on suppressive ART and HIV-unexposed, uninfected adolescents in Uganda. Carotid intima-media thickness (IMT) was increased in PHIV, suggesting a higher CVD risk. Flow cytometry analysis revealed greater activation, memory, and migratory capabilities of NK cells, and increased pro-inflammatory intermediate monocytes in PHIV, and these were supported by transcriptomics. Many of these innate immune cell subsets displayed associations with carotid IMT. Plasma oxidized-LDL (Ox-LDL) was significantly lower among PHIVs, and negatively correlated with pro-inflammatory, memory-like NK subsets. We demonstrated increased uptake of Ox-LDL by macrophages in the presence of activated, memory-like NK cells in vitro, suggesting a possible mechanism for greater CVD risk in PHIV. Collectively, our data demonstrate associations between dysregulated NK cell signatures and increased CVD risk among PHIV adolescents.