Single cell analyses of the HIV reservoir in the CNS and CSF: recent insights and implications

This review highlights recent advances in single cell "-omics" technologies that have transformed our understanding of the HIV reservoir in the central nervous system (CNS) and cerebrospinal fluid (CSF).

Recent studies have applied single cell and single nucleus RNA-seq, ATAC-seq, CITE-seq, AIRR-seq, multiomic platforms, and spatial transcriptomics to postmortem brain tissues and CSF. These analyses have revealed that HIV persists in rare subsets of CNS-resident microglia and trafficking CD4 + T cells despite ART. Infected microglia often display inflammatory transcriptional states, while clonal T cell populations harboring HIV can migrate between blood and CSF. Spatial and multimodal approaches are uncovering both the tissue localization and epigenetic regulation of infected cells, offering unprecedented insight into reservoir biology and neuropathogenesis.

Single cell studies have established the CNS as a transcriptionally active and clonally maintained reservoir of HIV during ART. These findings underscore the need for cure strategies that penetrate the brain, target both lymphoid and myeloid reservoirs, and consider the transcriptional, epigenetic and spatial context of HIV-infected cells. Ongoing technological advances will further illuminate the dynamics of the CNS reservoir and guide the design of diagnostic, prognostic and therapeutic biomarkers and CNS-penetrant therapeutic interventions.