Single-cell transcriptional landscapes reveal HIV-1-driven aberrant host gene transcription as a potential therapeutic target

Runxia Liu, Yang Hui Jimmy Yeh, Ales Varabyou, Jack A. Collora, Scott Sherrill-Mix, C. Conover Talbot, Sameet Mehta, Kristen Albrecht, Haiping Hao, Hao Zhang, Ross A. Pollack, Subul A. Beg, Rachela M. Calvi, Jianfei Hu, Christine M. Durand, Richard F. Ambinder, Rebecca Hoh, Steven G. Deeks, Jennifer Chiarella, Serena SpudichDaniel C. Douek, Frederic D. Bushman, Mihaela Pertea, Ya Chi Ho

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Understanding HIV-1-host interactions can identify the cellular environment supporting HIV-1 reactivation and mechanisms of clonal expansion. We developed HIV-1 SortSeq to isolate rare HIV-1-infected cells from virally suppressed, HIV-1-infected individuals upon early latency reversal. Single-cell transcriptome analysis of HIV-1 SortSeq+ cells revealed enrichment of nonsense-mediated RNA decay and viral transcription pathways. HIV-1 SortSeq+ cells up-regulated cellular factors that can support HIV-1 transcription (IMPDH1 and JAK1) or promote cellular survival (IL2 and IKBKB). HIV-1-host RNA landscape analysis at the integration site revealed that HIV-1 drives high aberrant host gene transcription downstream, but not upstream, of the integration site through HIV-1-to-host aberrant splicing, in which HIV-1 RNA splices into the host RNA and aberrantly drives host RNA transcription. HIV-1-induced aberrant transcription was driven by the HIV-1 promoter as shown by CRISPR-dCas9-mediated HIV-1-specific activation and could be suppressed by CRISPR-dCas9-mediated inhibition of HIV-1 5′ long terminal repeat. Overall, we identified cellular factors supporting HIV-1 reactivation and HIV-1-driven aberrant host gene transcription as potential therapeutic targets to disrupt HIV-1 persistence.

Original languageEnglish (US)
Article numbereaaz0802
JournalScience Translational Medicine
Volume12
Issue number543
DOIs
StatePublished - May 13 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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