PR002994 (Project)

Description:This project investigates early brain viral reservoir establishment and associated metabolic dysregulation following neonatal simian immunodeficiency virus (SIV) infection, with a focus on identifying critical windows for therapeutic intervention. Using a neonatal rhesus macaque model, we examined viral dynamics, neuropathology, and cerebrospinal fluid (CSF) metabolomic alterations during the earliest stages of infection and in response to early antiretroviral therapy (ART). We found that, unlike rapid viral dissemination in peripheral tissues, brain viral reservoirs were not consistently established until after 3 days post infection. During this early period, neonates exhibited minimal neuroinflammation and neuropathological changes. In contrast, profound metabolic dysregulation in CSF emerged rapidly, characterized by alterations in energy metabolism, neurotransmitter pathways, and oxidative stress–related metabolites, including kynurenine, phosphocreatine, and sorbitol. Importantly, early ART initiation, particularly at 3 days post infection, largely reversed these metabolic abnormalities. These findings highlight a critical early therapeutic window to prevent brain reservoir establishment and preserve central nervous system development, providing important insights for early intervention strategies in pediatric HIV infection.