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Single cell RNA-sequencing-based analysis of CD4(+) T-cell subset-specific susceptibility to transcriptional modulation by HIV-1 latency-reversing agents

Item Type:Preprint
Title:Single cell RNA-sequencing-based analysis of CD4(+) T-cell subset-specific susceptibility to transcriptional modulation by HIV-1 latency-reversing agents
Creators Name:Kazmierski, J. and Postmus, D. and Wyler, E. and Fischer, C. and Jansen, J. and Meixenberger, K. and Vitcetz, S.N. and Sohn, M. and Sauer, S. and Bannert, N. and Landthaler, M. and Goffinet, C.
Abstract:Shock-and-kill is one of the conceptually most advanced strategy towards establishment of an HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors with chromatin-remodeling capabilities, combined with anti-retroviral therapy, reactivates HIV-1 transcription in vivo. However, LRA treatment fails to significantly reduce the HIV-1 reservoir in HIV-1-positive individuals, indicating that it is probably insufficient to eliminate latently infected cells. The global and T-cell subset-specific impact of individual LRAs on the transcriptome of CD4(+) T-cells, the main HIV-1 reservoir containing cell type in vivo, remains understudied. Here, using single cell RNA-sequencing, we characterize LRA treatment-induced alterations of CD4 (+) T-cell subset composition and of subpopulation-specific transcriptomes, using Vorinostat and Panobinostat as two prototypic HDAC inhibitors. Ex vivo exposure of CD4(+) T-cells from an aviremic HIV-1-positive individual to Panobinostat markedly reduced the percentage of T(REG)cells. Furthermore, it altered expression of a multitude of interferon-regulated genes, resulting in suppression of several well-characterized antiviral genes, and in enhancement of selected interferon-regulated genes with proviral activities. These changes were most pronounced in T(N), T(CM), T(TM) and T(EM), and less pronounced in T(REG). Exposure to Vorinostat resulted in a comparably mild change of cellular transcriptomic profile, regarding both the number of deregulated genes and their fold change of expression. Nevertheless, selected interferon-regulated genes exhibited a subset-specific expression profile upon Vorinostat treatment. Finally, some genes were deregulated by both treatments in a subset-specific manner. We conclude that treatment by both individual HDAC inhibitors induces an overall proviral milieu in CD4(+) T-cells subsets. While this proviral state might be favorable for efficient HIV-1 reactivation, we hypothesize that it may impede the instruction of activation of cellular and adaptive immunity required for effective killing of reactivated cells.
Keywords:HIV-1, Latency-Reversing Agents, CD4(+) T-Cells, Interferon, Interferon-Regulated Genes, Single Cell-RNA Sequencing
Title of Book:Single Cell RNA-Sequencing-based Analysis of CD4+ T-Cell Subset-Specific Susceptibility to Transcriptional Modulation by HIV-1 Latency-Reversing Agents
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.05.04.075119
Date:5 May 2020
Official Publication:https://doi.org/10.1101/2020.05.04.075119

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