Research ArticleHIV

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

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Science Translational Medicine  13 May 2020:
Vol. 12, Issue 543, eaaz0802
DOI: 10.1126/scitranslmed.aaz0802

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Sorting out HIV

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.

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