Molecular Signatures of HIV-Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV.
- 1Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas, USA.
- 2Department of Veterinary Integrative Biosciences, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- 3Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Abstract
HIV-associated neurological complications remain a major concern in people living with HIV (PWH), even under effective viral suppression with combination antiretroviral therapy (cART), underscoring unresolved mechanisms driving HIV-related neurodegeneration. To address this gap, we used HIV-1-infected human cerebral organoids (hCOs) containing microglia as a physiologically relevant three-dimensional model of the central nervous system (CNS) and validated key findings in the brain region of simian immunodeficiency virus (SIV)-infected, cART-treated rhesus macaque model. Integrated single-nucleus RNA sequencing with ATAC-seq (multi-omics), identifies cell-type-specific alterations in dual innate immune-driven inflammatory signaling pathways across neural and glial populations in hCOs. Microglia were preferentially infected and activated, initiating IL-17A-mediated cascades involving IFN-γ/STAT1, CEBPB, and NF-κB signaling. These pathways converged with cGAS-STING and Notch-NEURL1 signaling, both associated with neuroinflammation and synaptic dysfunction. cART suppressed viral replication, reduced IL-17A-mediated neuroinflammation, improved mitochondrial function, and restored synaptic gene expression. Collectively, these findings identify dysregulation of IL-17A, STAT1, CEBPB, and cGAS-STING signaling as key molecular drivers of HIV-associated neuroinflammation. They also establish a potential mechanistic link between IL-17A signaling and microglial remodeling, providing a translational framework for the development of CNS-targeted therapies in PWH.
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BibTeX
@article{chennakesavan2026molecular,
title = {{Molecular Signatures of HIV-Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV.}},
author = {Karthick Chennakesavan and Malaroviyam Samikkannu and Shreyan Gupta and Olasunkanmi Israel Tayo and Arpan Acharya and James J Cai and Siddappa N Byrareddy and Thangavel Samikkannu},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.77954},
url = {https://europepmc.org/article/MED/42893406},
note = {CC BY},
}
RIS
TY - JOUR
TI - Molecular Signatures of HIV-Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV.
AU - Karthick Chennakesavan
AU - Malaroviyam Samikkannu
AU - Shreyan Gupta
AU - Olasunkanmi Israel Tayo
AU - Arpan Acharya
AU - James J Cai
AU - Siddappa N Byrareddy
AU - Thangavel Samikkannu
PY - 2026
DA - 2026/10/18
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.77954
UR - https://europepmc.org/article/MED/42893406
AB - HIV-associated neurological complications remain a major concern in people living with HIV (PWH), even under effective viral suppression with combination antiretroviral therapy (cART), underscoring unresolved mechanisms driving HIV-related neurodegeneration. To address this gap, we used HIV-1-infected human cerebral organoids (hCOs) containing microglia as a physiologically relevant three-dimensional model of the central nervous system (CNS) and validated key findings in the brain region of simian immunodeficiency virus (SIV)-infected, cART-treated rhesus macaque model. Integrated single-nucleus RNA sequencing with ATAC-seq (multi-omics), identifies cell-type-specific alterations in dual innate immune-driven inflammatory signaling pathways across neural and glial populations in hCOs. Microglia were preferentially infected and activated, initiating IL-17A-mediated cascades involving IFN-γ/STAT1, CEBPB, and NF-κB signaling. These pathways converged with cGAS-STING and Notch-NEURL1 signaling, both associated with neuroinflammation and synaptic dysfunction. cART suppressed viral replication, reduced IL-17A-mediated neuroinflammation, improved mitochondrial function, and restored synaptic gene expression. Collectively, these findings identify dysregulation of IL-17A, STAT1, CEBPB, and cGAS-STING signaling as key molecular drivers of HIV-associated neuroinflammation. They also establish a potential mechanistic link between IL-17A signaling and microglial remodeling, providing a translational framework for the development of CNS-targeted therapies in PWH.
SN - 2198-3844
ER -