HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model

The central nervous system (CNS) is a major human immunodeficiency virus type-1 (HIV-1) reservoir. Microglia are the primary target cell of HIV-1 infection in the CNS. Current models have not allowed the precise molecular pathways of acute and chronic CNS microglial infection to be tested with in vivo genetic methods. Here, we describe a novel-humanized mouse model utilizing human induced pluripotent stem cell (iPSC)derived microglia to xenograft into murine hosts. These mice are additionally engrafted with human peripheral blood mononuclear cells that serve as a medium to establish a peripheral infection that then spreads to the CNS microglia xenograft, modeling a trans-blood-brain barrier route of acute CNS HIV-1 infection with human target cells. The approach is compatible with iPSC genetic engineering, including inserting targeted transgenic reporter cassettes to track the xenografted human cells, enabling the testing of novel treatment and viral tracking strategies in a comparatively simple and cost-effective in vivo model for neuroHIV.