Sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids
Andrew J. Boreland,
Alessandro C. Stillitano,
Hsin-Ching Lin,
Yara Abbo,
Ronald P. Hart,
Peng Jiang,
Zhiping P. Pang,
Arnold B. Rabson
Affiliations
Andrew J. Boreland
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA; Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08854, USA
Alessandro C. Stillitano
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
Hsin-Ching Lin
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
Yara Abbo
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
Ronald P. Hart
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
Peng Jiang
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
Zhiping P. Pang
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA; Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08854, USA; Corresponding author
Arnold B. Rabson
Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA; Departments of Pharmacology, Pathology & Laboratory Medicine, and Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA; Corresponding author
Summary: 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.
