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

2024; Cell Press; Volume: 27; Issue: 5 Linguagem: Inglês

10.1016/j.isci.2024.109628

2589-0042

Andrew J. Boreland, Alessandro C. Stillitano, Hsin‐Ching Lin, Yara Abbo, Ronald P. Hart, Peng Jiang, Zhiping P. Pang, Arnold B. Rabson,

Reproductive System and Pregnancy

Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) affects up to half of people living with HIV-1 and causes long term neurological consequences. The pathophysiology of HIV-1-induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC)-derived microglia combined with sliced neocortical organoids. Incubation of microglia with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2) elicited productive infection and inflammatory activation. RNA sequencing revealed significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate a role for persistent type I interferon signaling in HIV-1-infected microglia in a human neural model, suggesting its potential significance in the pathogenesis of HAND.