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

Abstract

The central nervous system (CNS) is a major human immunodeficiency virus type 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-derived microglia to xenograft into murine hosts. These mice are additionally engrafted with human peripheral blood mononuclear cells that served as a medium to establish a peripheral infection that then spread 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 way vivo model for neuroHIV.

Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

“…Moreover, these infected microglia have been effectively cocultured in various model systems, including human stem cell-derived neural tricultures, 14 , 50 primary neuron progenitor cell-derived organoids, 51 iPSC-derived cerebral organoids, 52 and a humanized mouse model. 53 …”

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

“…Recent studies have demonstrated the feasibility of infecting iPSC-derived macrophages (Vaughan-Jackson et al 2021) and microglia (Rai et al 2020) with HIV-1. Moreover, these infected microglia have been effectively cocultured in various model systems, including human stem cell derived neural tricultures (Alvarez-Carbonell et al 2020;Ryan et al 2020), primary neuron progenitor cell derived organoids (dos Reis et al 2020), iPSC-derived cerebral organoids (Gumbs et al 2022), and a humanized mouse model (Min et al 2023).…”