TLR3 Activation of Microglia-Containing Cerebral Organoid Induces Antiviral Factors against HIV-1 Infection

Human induced pluripotent stem cell (iPSC)-derived cerebral organoids have been increasingly used as a brain model for studying various neurological disorders and neurotropic virus infections, including HIV-1. However, it is unclear whether iPSC-derived cerebral organoids possess functional innate antiviral immunity against HIV-1. In this study, we examined Toll-Like Receptor 3 (TLR3) activation and its role in the induction of IFNs and IFN-stimulated genes (ISGs) against HIV-1 in human iPSC-derived microglia containing cerebral organoids (MCOs). We observed that MCOs possess functional TLR3, which could be effectively activated by poly I:C. TLR3 activation of MCOs resulted in HIV-1 inhibition and induction of IFN-{beta}/IFN-{lambda}, antiviral ISGs (MX1, MX2, GBP5, SAMHD1, Viperin, and ISG56), and CC chemokines (MIP-1, MIP-1{beta}, and RANTES), the ligands for HIV entry coreceptor CCR5. This TLR3 activation-mediated anti-HIV-1 effects could be blocked by a specific TLR3 inhibitor. These findings indicate that human iPSC-derived MCOs are a suitable model for investigation of brain immunity and HIV-1 infection.