A Novel Glia-immune humanized mouse model for investigation of HIV CNS infection and neuroinflammation 4485

Abstract Description Although combined antiretroviral therapy (ART) is successful, HIV persists in reservoirs, including the central nervous system (CNS). Current models, such as HSC-reconstituted humanized mice, lack matched human glia in the brain, limiting insights into HIV CNS infection and pathogenesis. We developed a novel glia-immune humanized mouse model integrating human glial cells (astrocytes, oligodendroglia, and microglia-like cells) in the brain with donor-matched human immune reconstitution in peripheral blood and lymphoid tissues. Neonatal NSG mice were injected intrahepatically with HSCs and intracranially with donor-matched glia. We observed extensive engraftment of human glia in key CNS regions, including the cerebral cortex and hippocampus. The glia-immune mice supported robust HIV-1CH040 replication in both the periphery and CNS. HIV-infected mice exhibited heightened inflammation and elevated type I interferon-stimulated genes (ISGs) in peripheral and brain tissues. Bulk RNAseq revealed significant transcriptional changes in human glia, such as upregulation of ISGs, inflammasome-associated genes, and downregulation of transcriptional regulators linked to HIV latency. This model allows interrogation of glial transcriptomic changes and neuron-immune interactions, offering insights into HIV CNS infection, pathology, and therapeutic strategies targeting CNS HIV reservoirs and neuroinflammatory pathways. Funding Sources The work is funded by NIH R01 DA052841, NIH R01 AI172727, NIH R01 DA05987. Topic Categories Neuroimmunology (NEUR)