{
  "abstract": "Recent efforts to employ ectopic Tat as a latency-reversal strategy can benefit from the identification of Tat variants with more efficient transactivation activity. Tat primarily serves as a recruiter of the host transcription elongation factor P-TEFb to proviral HIV to stimulate transcription elongation. Tat can also functionally interact with a host of chromatin-modifying enzymes to promote HIV transcription initiation. In actively dividing T cells, P-TEFb is kept inactive by the 7SK snRNP complex. Although Tat is capable of physically extracting P-TEFb from 7SK snRNP as well as forming an assembly with the sequestrator complex, it is unclear whether Tat:7SK snRNP (Tat:7SK) is a reversible functional intermediate that mediates the recruitment of P-TEFb to proviral HIV. This study explored the reversibility of Tat:7SK and whether Tat clade variants differ in their ability to assemble this complex, mobilize P-TEFb and transactivate latent HIV. While the ectopic expression of clade B NL4-3 Tat caused a substantial dissociation of P-TEFb from 7SK snRNP, affinity tag-based immunoprecipitation experiments confirmed the assembly of Tat:7SK with the displacement of the P-TEFb inhibitory component HEXIM1. The P-TEFb kinase inhibitor flavopiridol (FVP), known to rapidly dissociate P-TEFb from 7SK snRNP, also induced the efficient release of Tat:P-TEFb from Tat:7SK, suggesting that P-TEFb remains a component of this latter complex. While Tat variants representing clades A, B, C and CRF_AE exhibited comparable binding to P-TEFb, clade D Tat showed the least binding. Unlike clades B and CRF_AE, clades A and C Tat associated much more weakly with the core 7SK snRNP subunits MEPCE and LARP7, indicating that their bound P-TEFb is likely liberated. Evaluation of latent HIV reactivation in the Jurkat 2D10 clonal model revealed a rapid loss of Tat transactivation capacity over time across all clades examined, with the most striking disparity observed between Clades A and D. Overall, our findings reveal substantial clade-specific differences in Tat's ability to liberate P-TEFb from 7SK snRNP and transactivate latent HIV, with the clade A variant displaying the highest potency. Contrary to the prevailing paradigm that Tat:7SK is a \"dead-end\" complex that is unable to avail P-TEFb for transcriptional control, we show that it is a reversible intermediate from which Tat:P-TEFb can be released en bloc.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular Biology & Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.",
    "Department of Biology, University of Puerto Rico, Mayaguez 00681, Puerto Rico."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Amie Donner",
      "orcid": "0009-0007-2945-6975"
    },
    {
      "affs": [
        0
      ],
      "name": "Taebin Son"
    },
    {
      "affs": [
        0
      ],
      "name": "Sanjna Boda"
    },
    {
      "affs": [
        0
      ],
      "name": "Claire T Kenney"
    },
    {
      "affs": [
        0
      ],
      "name": "Alexis Chiandussi",
      "orcid": "0009-0000-3869-7219"
    },
    {
      "affs": [
        1
      ],
      "name": "Rania Rodríguez"
    },
    {
      "affs": [
        0
      ],
      "name": "Jonathan Karn"
    },
    {
      "affs": [
        0
      ],
      "name": "Uri Mbonye",
      "orcid": "0000-0002-7694-0803"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9e07bt4f7wsmf.bib",
  "cited_by": 0,
  "doi": "10.3390/v18101137",
  "fulltext_url": "https://europepmc.org/articles/PMC13709444",
  "id": "9e07bt4f7wsmf",
  "issns": [
    "1999-4915"
  ],
  "landing_url": "https://europepmc.org/article/MED/42944057",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2406|HIV Research and Treatment"
    ]
  ],
  "openalex": "W7221768596",
  "pdf_url": "https://europepmc.org/articles/PMC13709444?pdf=render",
  "pmcid": "PMC13709444",
  "pmid": "42944057",
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9e07bt4f7wsmf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:12Z",
      "native_id": "MED:42944057",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42944057"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2406|HIV Research and Treatment",
      "subfield": "microbiology"
    }
  ],
  "title": "HIV-1 Tat Forms a Dissociable Complex with 7SK snRNP and Exhibits Clade Differences in Reversing the Sequestration of P-TEFb.",
  "title_text": "HIV-1 Tat Forms a Dissociable Complex with 7SK snRNP and Exhibits Clade Differences in Reversing the Sequestration of P-TEFb.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:12Z",
  "url": "https://research.draconitic.com/paper/9e07bt4f7wsmf",
  "venue": "Viruses",
  "versions": []
}