Persistent Microglial HIV Infection Drives Neuroinflammation Despite Viral Suppression: Insights from Rapid Postmortem Brain Biopsies
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Despite suppressive antiretroviral therapy (ART), HIV persists in the central nervous system (CNS) and contributes to HIV-associated neurocognitive disorder (HAND), but cell type–specific effects remain poorly defined. Using fluorescence-activated nuclei sorting of postmortem brain tissue of aviremic and viremic deceased people with HIV (DPWH) and HIV-negative individuals, we quantified the size of the HIV CNS reservoir and transcriptional alterations. Microglia were identified as the dominant CNS reservoir, harboring 10³–10⁴ HIV DNA copies per million cells by ddPCR-LTR assay in both aviremic and viremic DPWH. Bulk RNA-sequencing revealed immune pathway upregulation specifically in microglia, and downregulation of synaptic and homeostatic pathways across cell-types in viremic compared to aviremic individuals. ART partially mitigated microglial transcriptional dysregulation, but transcriptional profiles did not restore profiles to HIV-negative levels. Notably, persistent microglial infection was associated with transcriptional changes in other cell-types, underscoring microglia as a key therapeutical target for CNS-directed HIV cure strategies.
Authors: M. Nühn Marieke, Nadia Sabet, Nanouk Zuidmeer, C.J. van Abeelen Kirsten, E. Hermans Lucas, J. Schipper Pauline, Raphael Kübler, E. Basson Adriaan, Tanvier Omar, Ebrahim Variava, A. Martinson Neil, Stefanie Giacopazzi, D. F. Venter Willem, J. Muraro Mauro, M. J. Wensing Annemarie, D. de Witte Lot, A. Papathanasopoulos Maria, Monique Nijhuis, Jori Symons
Institutions: University Medical Center Utrecht, University of the Witwatersrand, Perinatal HIV Research Unit, Radboud University Medical Center, University of Cape Town, Groote Schuur Hospital, Icahn School of Medicine at Mount Sinai, Johannesburg Hospital, Johns Hopkins University, Single Cell Discoveries (Netherlands), Radboud University Nijmegen
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7162291828