Systems analysis by mass cytometry identifies susceptibility of latent HIV-infected T cells to targeting of p38 and mTOR pathways

Abstract

Efforts to cure HIV are hindered by viral persistence in latently infected memory CD4+ T cells.Targeting T cell death pathways dysregulated by HIV infection offers a novel approach for eradication of the latent reservoir. To identify potential therapeutic targets, we compared signaling and apoptosis in uninfected and latently infected primary cultured CD4+ central memory T cells by mass cytometry following T cell receptor stimulation. We found that HIV-infected cells were sensitized to activation of pro-apoptotic p38 kinase signaling via p53, and to inhibition of antiapoptotic mTOR kinase signaling, even without HIV protein expression. Simultaneous targeting of p38 and mTOR kinases in resting CD4+ T cells from virally-suppressed HIV+ patients ex vivo reduced cell-associated HIV RNA and DNA. Our results demonstrate how systems biology approaches are useful for identifying novel therapeutic approaches to treat HIV latency, and further suggest that it may be possible to deplete latent HIV-infected T cells without viral reactivation.

Linguistic Analysis of the bioRxiv Preprint Landscape

“…Examining the top five and bottom five preprints within the systems biology field reinforces PC1 ‘s dichotomous theme (Table 2). Preprints with the highest values [64,65,66,67,68] included software packages, machine learning analyses, and other computational biology manuscripts, while preprints with the lowest values [69,70,71,72,73] were focused on cellular signaling and protein activity. We provide the rest of our 50 generated PCs in our online repository (see Software and Data Availability).…”