HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells

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Abstract

HIV encodes Tat, a small protein that facilitates viral transcription by binding an RNA structure (TAR) formed on nascent viral pre-mRNAs. Besides this well characterized mechanism, Tat appears to modulate cellular transcription, but the target genes and molecular mechanisms remain poorly understood. We report here that Tat uses unexpected regulatory mechanisms to reprogram target immune cells to promote viral replication and rewire pathways beneficial for the virus. Tat functions through master transcriptional regulators bound at promoters and enhancers, rather than through cellular 'TAR-like' motifs, to both activate and repress gene sets sharing common functional annotations. Despite the complexity of transcriptional regulatory mechanisms in the cell, Tat precisely controls RNA Polymerase II recruitment and pause release to fine-tune the initiation and elongation steps. We propose that a virus with a limited coding capacity optimized its genome by evolving a small but 'multitasking' protein to simultaneously control viral and cellular transcription.

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Jonathan E Reeder

Biology, University of Texas at Dallas, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Youn-Tae Kwak

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Ryan P McNamara

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States

Competing interests
The authors declare that no competing interests exist.
Christian V Forst

Department of Genetics and Genomc Sciences, Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
The authors declare that no competing interests exist.
Iván D'Orso

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States

For correspondence
Ivan.Dorso@UTSouthwestern.edu

Competing interests
The authors declare that no competing interests exist.

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