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bioRxiv · 10.1101/2023.10.25.563950

Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids

Boreland, A. J.·Stillitano, A. C.·Lin, H.·Abbo, Y.·Hart, R. P.·Jiang, P.·Pang, Z. P.·Rabson, A. B.
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Abstract

Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge 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. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a 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 the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND. Highlights of the workO_LIHIV-1 productively infects iPSC-derived microglia and triggers inflammatory activation. C_LIO_LIHIV-1 infection of microglia results in sustained type I interferon signaling. C_LIO_LIMicroglia infected by HIV-1 incorporate into sliced neocortical organoids with persistent type I interferon signaling and disease risk gene expression. C_LI

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Boreland, A. J., Stillitano, A. C., Lin, H., Abbo, Y., Hart, R. P., Jiang, P., Pang, Z. P., Rabson, A. B.. 2023-10-25. Dysregulated neuroimmune interactions and sustained type I interferon signaling after human immunodeficiency virus type 1 infection of human iPSC derived microglia and cerebral organoids. https://doi.org/10.1101/2023.10.25.563950

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