New horizons in HIV neuropathogenesis: thinking beyond the brain

PURPOSE OF REVIEW: Neurocognitive disorders and neuropathology continue to affect a subset of people with HIV (PWH) despite long-term viral suppression with antiretroviral therapy (ART). The mechanisms driving persistent neuropathology remain incompletely defined, and current therapeutic options are largely nonspecific and patient-dependent. This review analyses emerging evidence on HIV-associated neuropathology in ART-suppressed PWH, with a particular focus on the role of the gut-brain axis. RECENT FINDINGS: Recent studies demonstrate that the CNS is a stable and transcriptionally active tissue reservoir, which may sustain chronic microglial activation, pro-inflammatory signalling, and synaptic injury. In parallel, accumulating evidence implicates systemic inflammation and gut barrier dysfunction as key contributors to neuroinflammation, linking microbial translocation and gut-brain axis perturbations to cognitive decline in PWH. Furthermore, persistent gut inflammation may result in enteric nervous system (ENS) dysfunction and aberrant signals that directly results in neuroinflammation and neuropathology. These mechanistic insights have driven evaluation of adjunctive strategies targeting HIV transcription and inflammatory pathways as potential approaches to limit neuropathogenesis. SUMMARY: Neuropathology in ART-suppressed PWH arises from convergent processes involving CNS HIV reservoirs, myeloid-driven neuroinflammation, systemic immune activation and gut-derived injury, rather than residual brain infection alone. Defining the relative contribution of these pathways in PWH and developing CNS-penetrant interventions that silence viral transcription, restore gut integrity and dampen systemic inflammation, will be critical to preventing and treating HIV-associated neuropathology.