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

doi:10.1016/j.isci.2024.109628

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

iScience. 2024 Mar 28;27(5):109628. doi: 10.1016/j.isci.2024.109628. eCollection 2024 May 17.

Authors

Andrew J Boreland^{1

2}, Alessandro C Stillitano¹, Hsin-Ching Lin¹, Yara Abbo¹, Ronald P Hart³, Peng Jiang³, Zhiping P Pang^{1

2}, Arnold B Rabson^{1

4}

Affiliations

¹ Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
² Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08854, USA.
³ Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
⁴ Departments of Pharmacology, Pathology & Laboratory Medicine, and Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.

Abstract

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.

Keywords: Cell biology; Immunology; Molecular biology; Neuroscience.

Abstract

Grants and funding