Targeting Tat inhibitors in the assembly of human immunodeficiency virus type 1 transcription complexes

Iván D'Orso, Jocelyn R. Grunwell, Robert L. Nakamura, Chandreyee Das, Alan D. Frankel

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Human immunodeficiency virus type 1 (HIV-1) transcription is regulated by the viral Tat protein, which relieves a block to elongation by recruiting an elongation factor, P-TEFb, to the viral promoter. Here, we report the discovery of potent Tat inhibitors that utilize a localization signal to target a dominant negative protein to its site of action. Fusing the Tat activation domain to some splicing factors, particularly to the Arg-Ser (RS) domain of U2AF65, creates Tat inhibitors that localize to subnuclear speckles, sites where pre-mRNA processing factors are stored for assembly into transcription complexes. A U2AF65 fusion named T-RS interacts with the nonphosphorylated C-terminal domain of RNA polymerase II (RNAP II) via its RS domain and is loaded into RNAP II holoenzyme complexes. T-RS is recruited efficiently to the HIV-1 promoter in a TAR-independent manner before RNAP II hyperphosphorylation but not to cellular promoters. The "preloading" of T-RS into HIV-1 preinitiation complexes prevents the entry of active Tat molecules, leaving the complexes in an elongation-incompetent state and effectively suppressing HIV-1 replication. The ability to deliver inhibitors to transcription complexes through the use of targeting/localization signals may provide new avenues for designing viral and transcription inhibitors.

Original languageEnglish (US)
Pages (from-to)9492-9504
Number of pages13
JournalJournal of virology
Volume82
Issue number19
DOIs
StatePublished - Oct 2008

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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