PT  - JOURNAL ARTICLE
AU  - Liu, Runxia
AU  - Yeh, Yang-Hui Jimmy
AU  - Varabyou, Ales
AU  - Collora, Jack A.
AU  - Sherrill-Mix, Scott
AU  - Talbot, C. Conover
AU  - Mehta, Sameet
AU  - Albrecht, Kristen
AU  - Hao, Haiping
AU  - Zhang, Hao
AU  - Pollack, Ross A.
AU  - Beg, Subul A.
AU  - Calvi, Rachela M.
AU  - Hu, Jianfei
AU  - Durand, Christine M.
AU  - Ambinder, Richard F.
AU  - Hoh, Rebecca
AU  - Deeks, Steven G.
AU  - Chiarella, Jennifer
AU  - Spudich, Serena
AU  - Douek, Daniel C.
AU  - Bushman, Frederic D.
AU  - Pertea, Mihaela
AU  - Ho, Ya-Chi
TI  - Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target
AID  - 10.1126/scitranslmed.aaz0802
DP  - 2020 May 13
TA  - Science Translational Medicine
PG  - eaaz0802
VI  - 12
IP  - 543
4099  - http://stm.sciencemag.org/content/12/543/eaaz0802.short
4100  - http://stm.sciencemag.org/content/12/543/eaaz0802.full
AB  - The latent reservoir of HIV-1–infected cells that persist in, otherwise, virally suppressed individuals constitutes the major barrier to cure. Liu et al. developed a method called HIV-1 SortSeq to identify rare HIV-infected CD4+ T cells from individuals on antiretroviral therapies upon latency reversal ex vivo. Analysis of the isolated single cells showed that the 5′ long terminal repeat of HIV-1 was capable of driving the transcription of host genes downstream of the integration site, which may contribute to HIV persistence.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.