Activation of HIV-1 proviruses increases downstream chromatin accessibility

Raven Shah; Christian M Gallardo; Yoonhee H Jung; Ben Clock; Jesse R Dixon; William M McFadden; Kinjal Majumder; David J Pintel; Victor G Corces; Bruce E Torbett; Philip R Tedbury; Stefan G Sarafianos

doi:10.1016/j.isci.2022.105490

Activation of HIV-1 proviruses increases downstream chromatin accessibility

iScience. 2022 Nov 8;25(12):105490. doi: 10.1016/j.isci.2022.105490. eCollection 2022 Dec 22.

Authors

Raven Shah^{1

2}, Christian M Gallardo³, Yoonhee H Jung⁴, Ben Clock⁵, Jesse R Dixon⁵, William M McFadden^{1

2}, Kinjal Majumder⁶, David J Pintel⁷, Victor G Corces⁴, Bruce E Torbett^{3

8}, Philip R Tedbury^{1

2}, Stefan G Sarafianos^{1

2}

Affiliations

¹ Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30329, USA.
² Children's Healthcare of Atlanta, Atlanta, GA 30329, USA.
³ Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
⁴ Department of Biology, Emory University, Atlanta, GA 30329, USA.
⁵ Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁶ Institute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Department of Molecular Microbiology and Immunology, Christopher S. Bond Life Sciences Center, University of Missouri School of Medicine, Columbia, MO 65211, USA.
⁸ Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA.

Abstract

It is unclear how the activation of HIV-1 transcription affects chromatin structure. We interrogated chromatin organization both genome-wide and nearby HIV-1 integration sites using Hi-C and ATAC-seq. In conjunction, we analyzed the transcription of the HIV-1 genome and neighboring genes. We found that long-range chromatin contacts did not differ significantly between uninfected cells and those harboring an integrated HIV-1 genome, whether the HIV-1 genome was actively transcribed or inactive. Instead, the activation of HIV-1 transcription changes chromatin accessibility immediately downstream of the provirus, demonstrating that HIV-1 can alter local cellular chromatin structure. Finally, we examined HIV-1 and neighboring host gene transcripts with long-read sequencing and found populations of chimeric RNAs both virus-to-host and host-to-virus. Thus, multiomics profiling revealed that the activation of HIV-1 transcription led to local changes in chromatin organization and altered the expression of neighboring host genes.

Keywords: Biological sciences; Chromosome organization; Molecular biology; Molecular interaction.

Abstract

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