Date Published:
2026 Jul

Publication Type:
Journal Article

Authors:

Rajnish S Dave
Ayo A Oludipe
Elizabeth C Pasipanodya
Seth Sherman
Steffanie H Wilson
Dana H Gabuzba
Melissa J Churchill
Thomas A Angelovich
Robert J Gorelick
Sara Gianella
Antoine Chaillon
Jerel Adam Fields
Susan Morgello
Benjamin B Gelman
David J Moore
Elyse J Singer
Beau M Ances
Howard S Fox

PMID:
42525639

URL:
https://pubmed.ncbi.nlm.nih.gov/42525639/

DOI:
10.1371/journal.ppat.1014446

Abstract:
HIV persistence within anatomical reservoirs remains the primary barrier to achieving an HIV cure. While antiretroviral therapy effectively suppresses plasma viremia, it does not eliminate integrated proviral genomes that persist in long-lived cellular compartments. The central nervous system (CNS) is a clinically important HIV reservoir, characterized by immune privilege and the persistence of tissue-resident infection despite effective antiretroviral therapy (ART). Evidence from postmortem studies reveals that HIV DNA, RNA, and even intact replication-competent proviruses remain detectable in brain tissue from virally suppressed people with HIV. Evidence derived primarily from in situ approaches and viable-cell studies supports myeloid-lineage reservoirs, particularly microglia and CNS-associated macrophages, as key cellular sources of persistence, while the extent and biological relevance of astrocyte infection remains debated. These reservoirs exhibit transcriptional activity and are associated with chronic neuroinflammation, which may contribute to HIV-associated neurocognitive disorders, despite systemic viral suppression. Here, we synthesize recent findings from autopsy brain studies, including work enabled by major biorepositories, such as the National NeuroHIV Tissue Consortium and rapid-autopsy programs, including the Last Gift, both of which are essential for studying HIV reservoirs in the CNS. We summarize methodologies for detecting and characterizing HIV in brain tissue, highlight heterogeneous patterns of regional distribution and compartmentalization, and review emerging links between CNS persistence and neuroinflammation. We conclude with priorities for harmonized tissue processing, multi-modal single-cell and spatial profiling, and coordinated cross-cohort analyses to clarify the contribution of CNS reservoirs to neuroHIV pathogenesis and systemic rebound.