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

Although combined antiretroviral therapy (ART) is successful in suppressing viral replication, HIV persists in anatomic 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 in the brain with donor-matched human immune reconstitution in peripheral blood and lymphoid tissues. Neonatal NSG mice were injected intrahepatically with Hematopoietic Stem Cells (HSCs) and intracranially with donor-matched glia. We observed extensive engraftment of all three types of human glial cells (astrocytes, oligodendroglia, and microglia-like cells) in key CNS regions, including the cerebral cortex and hippocampus. These glia-immune mice supported robust HIV-1 replication in the peripheral blood, lymphoid tissues and CNS. HIV-infected mice exhibited heightened inflammation and elevated expression of 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 implicated in metabolic regulations and epigenetic controls. Overall, 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.