biostudies-literatureBoreland AJNCATSNCATS NIH HHSRutgers Brain Health InstituteNIAAA NIH HHSNINDS NIH HHSRutgers UniversityNIGMS NIH HHSRobert Wood Johnson FoundationNIGMSNINDS109628https://www.ebi.ac.uk/biostudies/studies/S-EPMC11019286biostudies-literatureUnknown27(5)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 neociScienceSustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids.PMC11019286R01 AA023797T32 GM135141R21 NS120806TL1 TR003019T32 GM008339Lin HCHart RPStillitano ACAbbo YPang ZPRabson ABBoreland AJJiang PfalseSustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids.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 neoc2024-01-01T00:00:00Z2024 May2026-06-01T11:53:19.412Z2025-04-22T13:47:25.866ZS-EPMC110192863862896110.1016/j.isci.2024.109628