Work

The human chromatin remodeling complex p400 restricts HIV-1 transcription in a Tat-dependent manner

Year: 2025

Type: article

Abstract: The chromatin landscape surrounding integrated HIV proviruses critically shapes viral transcription. We systematically examined ATP-dependent chromatin remodeling complexes (SWI/SNF, ISWI, CHD, and INO80) as regulators of HIV expression and identified the p400 complex, a member of the INO80 family, as a potent repressor. Depleting p400 subunits, including the EP400 ATPase and DMAP1, markedly increased HIV transcription and RNAPII elongation at the proviral locus. Mechanistically, EP400 associates with the RNAPII C-terminal domain, while DMAP1 directly engages the viral transactivator Tat, with repression requiring simultaneous interactions among EP400, DMAP1, and Tat. Loss of either EP400 or DMAP1 selectively increased infection and transcription of Tat-competent, but not Tat-deficient, viruses. Although p400 is recruited to active HIV chromatin via RNAPII in a Tat-independent manner, it restrains elongation once Tat accumulates during reactivation. DMAP1 binding to Tat's basic domain blocks Tat-TAR RNA interaction, thereby limiting p-TEFb-mediated RNAPII Ser2 phosphorylation and elongation. Thus, the p400 complex functions as a host restriction factor that limits Tat-dependent HIV transcription via a Tat-dependent proximal mechanism, highlighting the p400-Tat interface as a potential target for HIV cure strategies.

Source: Nucleic Acids Research

DOI: 10.1093/nar/gkaf1323