RT Journal Article
SR Electronic
T1 Neuroinflammation and EIF2 signaling persist in an HiPSC tri-culture model of HIV infection despite antiretroviral treatment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 779025
DO 10.1101/779025
A1 Sean K. Ryan
A1 Michael V. Gonzalez
A1 James P. Garifallou
A1 Frederick C. Bennett
A1 Kimberly S. Williams
A1 Hakon Hakonarson
A1 Stewart A. Anderson
A1 Kelly L. Jordan-Sciutto
YR 2019
UL http://biorxiv.org/content/early/2019/09/24/779025.abstract
AB 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.