Brain viral reservoir seeding and neurological metabolic dysregulation in early-life immunodeficiency virus infection.

While viral reservoirs establish rapidly in the peripheral and lymphoid tissues in HIV-exposed and infected infants, the timing and consequences of viral seeding in the developing brain remain unclear. Using a neonatal rhesus macaque SIV model, we tracked early brain-associated viral DNA/RNA, neuropathology, and cerebrospinal fluid (CSF) metabolism, and evaluated the impact of early antiretroviral therapy (ART). CSF viral RNA was detectable by 2 days post infection (dpi), mirroring plasma viral load kinetics. In contrast, brain tissue SIV DNA and RNA remained largely undetectable through the first 3 days of infection. Despite this early viral dissemination, we observed no significant neuropathological lesions or CSF proinflammatory cytokine responses during the first week. However, marked CSF metabolic dysregulation emerged by 1 month post infection. Initiating ART early, specifically at 3 dpi, normalized these neurometabolic abnormalities. These findings demonstrate that CSF metabolomic shifts can occur independently of overt neuroinflammation during the early stages of viral seeding. These results support initiating ART as early as possible after perinatal HIV exposure to prevent the brain viral reservoir seeding and limit long-term neurological sequelae.