Central Nervous System Reservoirs and HIV Cure: Therapeutic Opportunities and Challenges

Despite viral suppression with antiretroviral therapy, people with HIV (PWH) remain at increased risk of neurocognitive impairment, neuroinflammation, and potential viral rebound following therapy interruption. Although the central nervous system (CNS) is a recognised HIV reservoir, it is often not fully considered in cure approaches.

HIV DNA and ongoing viral transcription persist in the CNS of ART-suppressed PWH, potentially contributing to neuroinflammation and neurocognitive dysfunction. HIV cure strategies, including latency-reversing/promoting agents, broadly neutralising antibodies and other approaches have varying degrees of CNS penetration, efficacy and potential neurotoxicity. Therefore, interventions aimed at silencing or eradicating HIV reservoirs require monitoring of both reservoir-targeting efficacy and neurological adverse effects. Greater consideration of CNS penetration, efficacy in targeting CNS reservoirs, and neurotoxicity is required in HIV cure studies. Developing CNS-inclusive strategies that minimise adverse neurological effects may be an important step in achieving HIV cure.