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

TY - JOUR

T1 - Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

AU - Boreland, Andrew J.

AU - Stillitano, Alessandro C.

AU - Lin, Hsin Ching

AU - Abbo, Yara

AU - Hart, Ronald P.

AU - Jiang, Peng

AU - Pang, Zhiping P.

AU - Rabson, Arnold B.

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024/5/17

Y1 - 2024/5/17

N2 - 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.

AB - 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.

KW - Cell biology

KW - Immunology

KW - Molecular biology

KW - Neuroscience

UR - http://www.scopus.com/inward/record.url?scp=85189963610&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85189963610&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2024.109628

DO - 10.1016/j.isci.2024.109628

M3 - Article

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 5

M1 - 109628

ER -