CD49a expression defines a metabolically robust, cytokine-biased liver NK cell subset in rhesus macaques during lentivirus infection.

Liver-resident natural killer (LrNK) cells are critical regulators of hepatic immune homeostasis and demonstrate antiviral activity, yet their role in lentivirus infections remains poorly defined. Using a rhesus macaque (RM) model of Simian immunodeficiency virus (SIV) and Simian-human immunodeficiency virus (SHIV) infections, we investigated the phenotypes, metabolic profiles and functional responses of hepatic NK cells across naïve, acutely SIV-infected and chronically SHIV-infected RM. We identified liver-resident (Lr) NK cells as CD3-CD159a/c+CD49a+, whereas CD3-CD159a/c+CD49a- NK cells include circulating NK cell subsets in the liver. Across infection states, CD49a+ LrNK cells exhibited elevated expression of activation markers, including NKG2D, NKp30, NKp46 and CD69, as well as increased expression of metabolic markers, including CD98, Glut1 and MitoTracker. In contrast, Ki-67 expression was reduced in CD49a+ LrNK cells compared with their CD49a- counterparts. Unsupervised clustering revealed that CD49a+ LrNK cells were also marked by high CD69 expression. While total NK cell cytokine secretion was elevated in acute SIV-infected animals, CD49a+ LrNK cells exhibited robust polyfunctional cytokine responses and reduced expression of the cytotoxic marker CD107a upon mitogen stimulation in comparison with CD49a- LrNK cells regardless of infection status. These findings reveal distinct metabolic and functional specialization of hepatic NK cell subsets, underscoring the unique phenotype and functions of CD49a+ LrNK cells in RM, which may offer novel insights and therapeutic opportunities for treating liver inflammation in HIV infection and other chronic liver diseases.