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

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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., Postmus, D., Wyler, E., Fischer, C., Jansen, J., Meixenberger, K., Vitcetz, S.N., Sohn, M., Sauer, S., Bannert, N., 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
Source:	bioRxiv
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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