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

Ryan, S. K.; Gonzalez, M. V.; Garifallou, J. P.; Bennett, F. C.; Williams, K. S.; Hakonarson, H. K.; Anderson, S. A.; Jordan-Sciutto, K. L.

doi:10.1101/779025

bioRxiv · 10.1101/779025

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

Ryan, S. K.·Gonzalez, M. V.·Garifallou, J. P.·Bennett, F. C.·Williams, K. S.·Hakonarson, H. K.·Anderson, S. A.·Jordan-Sciutto, K. L.

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Abstract

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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Ryan, S. K., Gonzalez, M. V., Garifallou, J. P., Bennett, F. C., Williams, K. S., Hakonarson, H. K., Anderson, S. A., Jordan-Sciutto, K. L.. 2019-09-24. Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment. https://doi.org/10.1101/779025

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