Daniel R. Ram, Raja Mohan Gopalakrishnan, Malika Aïd, Kyle Kroll, Jasmine Miftahof, Omar Aristizabal, Eunice Kayitare Gikundiro, Caitlin M. Davis, Marco M. Hefti, Kimberly L. Fiock, Brook Tilahun, Yvette Umutoniwase, Kate Loidolt, Christine M. Fennessey, Noe B. Mercado, Victoria Harper-Alexander, Rhianna Jones, Griffin Woolley, Valerie Varner, Michelle Lifton, S. Bosinger, Dan H. Barouch, B. Keele, R. Keith Reeves, C. Sabrina Tan
HIV-associated neurocognitive disorder (HAND) remains a significant complication in people living with HIV, with inflammation playing a central role in its pathogenesis. Understanding how the brain's immune network responds to lentiviral infection is therefore critical. We show that acute simian immunodeficiency virus (SIV) infection elicits a robust resident brain immune response in control animals, marked by enhanced microglial ramification. In contrast, animals pretreated with anti-interleukin (IL)-15 antibodies (αIL-15) before SIV mac239X infection display reduced neuroinflammation without altering brain viral burden. Peripheral IL-15 blockade decreases brain-infiltrating T lymphocytes, alters their spatial dynamics, suppresses proinflammatory cytokine (IL-6) expression in microglia, and increases anti-inflammatory cytokine (TGF-β) expression in brain macrophages. Transcriptomic profiling reveals a global reduction in inflammatory signaling and an upregulation of genes associated with M1 macrophage pathways. Together, these findings demonstrate that peripheral IL-15 modulation attenuates neuroinflammation during acute lentiviral infection and highlight IL-15 as a potential therapeutic target for neuroinflammatory conditions of the brain.