title: BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism.
abstract: The therapeutic potential of pharmacologic inhibition of bromodomain and extraterminal (BET) proteins has recently emerged in hematological malignancies and chronic inflammation. We find that BET inhibitor compounds (JQ1, I-Bet, I-Bet151 and MS417) reactivate HIV from latency. This is evident in polyclonal Jurkat cell populations containing latent infectious HIV, as well as in a primary T-cell model of HIV latency. Importantly, we show that this activation is dependent on the positive transcription elongation factor p-TEFb but independent from the viral Tat protein, arguing against the possibility that removal of the BET protein BRD4, which functions as a cellular competitor for Tat, serves as a primary mechanism for BET inhibitor action. Instead, we find that the related BET protein, BRD2, enforces HIV latency in the absence of Tat, pointing to a new target for BET inhibitor treatment in HIV infection. In shRNA-mediated knockdown experiments, knockdown of BRD2 activates HIV transcription to the same extent as JQ1 treatment, while a lesser effect is observed with BRD4. In single-cell time-lapse fluorescence microscopy, quantitative analyses across ~2,000 viral integration sites confirm the Tat-independent effect of JQ1 and point to positive effects of JQ1 on transcription elongation, while delaying re-initiation of the polymerase complex at the viral promoter. Collectively, our results identify BRD2 as a new Tat-independent suppressor of HIV transcription in latently infected cells and underscore the therapeutic potential of BET inhibitors in the reversal of HIV latency.
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, CA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Boehm
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvanese
authors.forename: Roy D
authors.initials: RD
authors.lastname: Dar
authors.forename: Sifei
authors.initials: S
authors.lastname: Xing
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schroeder
authors.forename: Laura
authors.initials: L
authors.lastname: Martins
authors.forename: Katherine
authors.initials: K
authors.lastname: Aull
authors.forename: Pao-Chen
authors.initials: PC
authors.lastname: Li
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
authors.forename: Leor
authors.initials: L
authors.lastname: Weinberger
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
mesh_terms: D001381:Azepines / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D057809:HEK293 Cells; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D017735:Virus Latency; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D001569:Benzodiazepines; D018797:Cell Cycle Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; D054322:tat Gene Products, Human Immunodeficiency Virus; C561695:(+)-JQ1 compound; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C568713:GSK1210151A; C554645:molibresib