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

Autor/innen

  • J. Kazmierski
  • D. Postmus
  • E. Wyler
  • C. Fischer
  • J. Jansen
  • K. Meixenberger
  • S.N. Vitcetz
  • M. Sohn
  • S. Sauer
  • N. Bannert
  • M. Landthaler
  • C. Goffinet

Journal

  • bioRxiv

Quellenangabe

  • bioRxiv

Zusammenfassung

  • 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.


DOI

doi:10.1101/2020.05.04.075119