SPP1+ Microglia Are Associated with Neuroimmune Rewiring and Glutamatergic Neuronal Injury in ART-Suppressed People Living with HIV
- 1The University of North Carolina at Chapel Hill
Abstract
Antiretroviral therapy (ART) effectively suppresses systemic HIV replication but does not eradicate viral reservoirs in the brain, where their identity and contribution to neurological injury remain poorly defined. Using bulk, single-cell, and single-nucleus transcriptomics of postmortem human brain tissue, we identify an activated SPP1 microglial population that expands 5.8-fold during ART and serves as the primary central nervous system (CNS) reservoir, preferentially harboring HIV transcripts. These reservoir microglia adopt a distinct, immune-evasive reprogramming state marked by chronic type I interferon signaling and inflammasome activation, which we recapitulate in primary human microglia via prolonged interferon-{beta} exposure. We show that viral transcription in ART-suppressed brains is dominated by nef, which may sustain the viral reservoir by disrupting host HLA-A and HLA-E presentation machinery. This persistent, immune-evasive state is associated with TREM2-C1QC complement-mediated synaptic pruning and severe DNA damage response dysregulation, culminating in a profound loss of VGLUT1 and GAD67 glutamatergic neurons that persists despite viral suppression. Our findings establish SPP1 microglia as an active, pathogenic CNS reservoir, identifying the SPP1, MHC-I, and complement pathways as therapeutic targets to eliminate viral persistence and reverse HIV-associated neurocognitive dysfunction.
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BibTeX
@misc{shabangu2026spp1,
title = {{SPP1+ Microglia Are Associated with Neuroimmune Rewiring and Glutamatergic Neuronal Injury in ART-Suppressed People Living with HIV}},
author = {C. S. Shabangu and H. Chen and M. Ashokkumar and N. Katuwal and J. B. Lovins and E. P. Browne and S. Gianella and A. Chaillon and D. M. Margolis and Y. Tang and G. Jiang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749241},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749241v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - SPP1+ Microglia Are Associated with Neuroimmune Rewiring and Glutamatergic Neuronal Injury in ART-Suppressed People Living with HIV
AU - C. S. Shabangu
AU - H. Chen
AU - M. Ashokkumar
AU - N. Katuwal
AU - J. B. Lovins
AU - E. P. Browne
AU - S. Gianella
AU - A. Chaillon
AU - D. M. Margolis
AU - Y. Tang
AU - G. Jiang
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749241
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749241v1
AB - Antiretroviral therapy (ART) effectively suppresses systemic HIV replication but does not eradicate viral reservoirs in the brain, where their identity and contribution to neurological injury remain poorly defined. Using bulk, single-cell, and single-nucleus transcriptomics of postmortem human brain tissue, we identify an activated SPP1 microglial population that expands 5.8-fold during ART and serves as the primary central nervous system (CNS) reservoir, preferentially harboring HIV transcripts. These reservoir microglia adopt a distinct, immune-evasive reprogramming state marked by chronic type I interferon signaling and inflammasome activation, which we recapitulate in primary human microglia via prolonged interferon-{beta} exposure. We show that viral transcription in ART-suppressed brains is dominated by nef, which may sustain the viral reservoir by disrupting host HLA-A and HLA-E presentation machinery. This persistent, immune-evasive state is associated with TREM2-C1QC complement-mediated synaptic pruning and severe DNA damage response dysregulation, culminating in a profound loss of VGLUT1 and GAD67 glutamatergic neurons that persists despite viral suppression. Our findings establish SPP1 microglia as an active, pathogenic CNS reservoir, identifying the SPP1, MHC-I, and complement pathways as therapeutic targets to eliminate viral persistence and reverse HIV-associated neurocognitive dysfunction.
ER -