Revisiting What HIV in the Brain Can Teach Us About SARS-CoV-2 Neurological Complications

In 2021, a Perspective article suggested that principles of HIV neuropathogenesis could provide a conceptual framework for understanding the neurological complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection when mechanistic evidence was limited. Five years later, extensive clinical, neuropathological, and experimental studies allow reassessment of that framework. Current evidence has shifted emphasis away from direct viral infection of the central nervous system toward host-mediated mechanisms involving persistent immune activation, endothelial dysfunction, glial activation, thromboinflammation, and disruption of the neuroimmune axis. At the same time, persistent viral antigens and adaptive immune responses, including autoantibodies in subsets of patients, have expanded our understanding of the biological heterogeneity underlying post-acute sequelae of SARS-CoV-2 infection with neurological manifestations. This Perspective revisits the original framework in light of these advances and examines how concepts derived from HIV neuropathogenesis continue to inform our understanding of persistent neurological dysfunction following SARS-CoV-2 infection.