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Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment

By Sean K. Ryan, Michael V Gonzalez, James P Garifallou, Frederick C Bennett, Kimberly S Williams, Hakon Hakonarson, Stewart A Anderson, Kelly L Jordan-Sciutto

Posted 24 Sep 2019
bioRxiv DOI: 10.1101/779025 (published DOI: 10.1016/j.stemcr.2020.02.010)

HIV-Associated Neurocognitive Disorders (HAND) affect over half of HIV-infected individuals worldwide, despite antiretroviral therapy (ART). Therapeutically targetable mechanisms underlying HAND remain elusive. We developed a human-induced pluripotent stem cell (HiPSC) based model; whereby, we independently differentiate HiPSCs into neurons, astrocytes, and microglia and systematically combine to generate a tri-culture with or without HIV-infection and ART. scRNAseq analysis on tri-cultures including HIV-infected microglia revealed inflammatory signatures in the microglia and EIF2 signaling in all three cell types. Remarkably, EFZ alone induced a similar response to infection. Treatment with the antiretroviral compound Efavirenz (EFZ) mostly resolved these signatures; However, EFZ increased RhoGDI and CD40 signaling in the HIV-infected microglia. This activation was associated with a persistent increase in TNFa expression. This work establishes a tri-culture that recapitulates key features of HIV infection in the CNS and provides a new model to examine the effects of HIV infection and its treatment with antiretrovirals.

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