Persistent Microglial HIV Infection Drives Neuroinflammation Despite Viral Suppression: Insights from Rapid Postmortem Brain Biopsies

Marieke M. Nühn; Nadia Sabet; Nanouk Zuidmeer; Kirsten C. J. van Abeelen; Lucas E. Hermans; Pauline J. Schipper; Raphael Kübler; Adriaan Erasmus Basson; Tanvier Omar; Ebrahim Variava; Neil Alexander Martinson; Stefanie Giacopazzi; Willem D F Venter; Mauro J. Muraro; Annemarie MJ Wensing; Lot D. de Witte; Maria Antonia Papathanasopoulos; Monique Nijhuis; Jori Symons

doi:10.64898/2026.05.20.726582

NeurosciencebioRxivMay 25, 2026

Preprint

Persistent Microglial HIV Infection Drives Neuroinflammation Despite Viral Suppression: Insights from Rapid Postmortem Brain Biopsies

Marieke M. Nühn iD, Nadia Sabet iD, Nanouk Zuidmeer iD, Kirsten C. J. van Abeelen iD, Lucas E. Hermans iD, Pauline J. Schipper iD, Raphael Kübler iD, Adriaan Erasmus Basson iD, Tanvier Omar iD, Ebrahim Variava iD, Neil Alexander Martinson iD, Stefanie Giacopazzi, Willem D F Venter iD, Mauro J. Muraro iD, Annemarie MJ Wensing, Lot D. de Witte iD, Maria Antonia Papathanasopoulos iD, Monique Nijhuis iD, Jori Symons iD

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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 103-10 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.