BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism
Daniela Boehm,Daniela Boehm,Vincenzo Calvanese,Vincenzo Calvanese,Roy D. Dar,Sifei Xing,Sebastian Schroeder,Sebastian Schroeder,Laura J. Martins,Katherine Aull,Katherine Aull,Pao-Chen Li,Pao-Chen Li,Vicente Planelles,James E. Bradner,Ming-Ming Zhou,Robert F. Siliciano,Leor S. Weinberger,Leor S. Weinberger,Eric Verdin,Eric Verdin,Melanie Ott,Melanie Ott +22 more
TLDR
BRD2 is identified 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.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 exte...read more
Citations
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Journal ArticleDOI
Targeting bromodomains: epigenetic readers of lysine acetylation
TL;DR: Recent progress in the development of bromodomain inhibitors is highlighted, and their potential applications in drug discovery are highlighted.
Journal ArticleDOI
The Mechanisms behind the Therapeutic Activity of BET Bromodomain Inhibition
Junwei Shi,Christopher R. Vakoc +1 more
TL;DR: The current understanding of molecular mechanisms that underlie the promising therapeutic effects of BET bromodomain inhibition are reviewed.
Posted Content
Stochastic Gene Expression in a Lentiviral Positive Feedback Loop: HIV-1 Tat Fluctuations Drive Phenotypic Diversity
Leor S. Weinberger,John C. Burnett,John C. Burnett,Jared E. Toettcher,Adam P. Arkin,Adam P. Arkin,David V. Schaffer,David V. Schaffer +7 more
TL;DR: Stochastic computational modeling successfully accounted for PheB and correctly predicted the dynamics of a Tat mutant that were subsequently confirmed by experiment, illustrating the importance of stochastic fluctuations in gene expression in a mammalian system.
Journal ArticleDOI
New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo
C. Korin Bullen,Gregory M. Laird,Christine M. Durand,Janet D. Siliciano,Robert F. Siliciano,Robert F. Siliciano +5 more
TL;DR: It is demonstrated that current in vitro models do not fully recapitulate mechanisms governing HIV-1 latency in vivo, and the data indicate that non-activating LRAs are unlikely to drive the elimination of the latent reservoir in vivo when administered individually.
Journal ArticleDOI
Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.
Julian Elliott,Fiona Wightman,Ajantha Solomon,Khader Ghneim,Jeffrey D. Ahlers,Mark J. Cameron,Miranda Zoe Denham Smith,Tim Spelman,James H McMahon,Pushparaj Velayudham,Gregor J. Brown,Janine Roney,Jo Watson,Miles Prince,Jennifer F Hoy,Nicolas Chomont,Rémi Fromentin,Francesco A. Procopio,Joumana Zeidan,Sarah Palmer,Lina Odevall,Ricky W. Johnstone,Ben P. Martin,Elizabeth Sinclair,Steven G. Deeks,Daria J. Hazuda,Paul U. Cameron,Rafick-Pierre Sekaly,Sharon R Lewin +28 more
TL;DR: Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients, however, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.
References
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Journal ArticleDOI
In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector
Luigi Naldini,Ulrike Blömer,Philippe Gallay,Daniel S. Ory,Richard C. Mulligan,Fred H. Gage,Inder M. Verma,Didier Trono +7 more
TL;DR: The ability of HIV-based viral vectors to deliver genes in vivo into nondividing cells could increase the applicability of retroviral vectors in human gene therapy.
Journal ArticleDOI
Selective inhibition of BET bromodomains.
Panagis Filippakopoulos,Jun Qi,Sarah Picaud,Yao Shen,William B. Smith,Oleg Fedorov,Elizabeth M. Morse,T. Keates,Tyler T. Hickman,I. Felletar,Martin Philpott,Shonagh Munro,Michael R. McKeown,Yuchuan Wang,Amanda L. Christie,Nathan West,Michael J. Cameron,Brian E. Schwartz,Tom D. Heightman,Nicholas B. La Thangue,Christopher A. French,Olaf Wiest,Andrew L. Kung,Stefan Knapp,Stefan Knapp,James E. Bradner +25 more
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Journal ArticleDOI
Latent infection of CD4 + T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy
Diana Finzi,Joel N. Blankson,Janet M. Siliciano,Joseph B. Margolick,Karen Chadwick,Theodore C. Pierson,Kendall A. Smith,Julianna Lisziewicz,Franco Lori,Charles Flexner,Thomas C. Quinn,Richard E. Chaisson,Eric S. Rosenberg,Bruce D. Walker,Stephen J. Gange,Joel E. Gallant,Robert F. Siliciano +16 more
TL;DR: The mean half-life of the latent reservoir was very long (43.9 months) and the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable as mentioned in this paper.
Journal ArticleDOI
Suppression of inflammation by a synthetic histone mimic
Edwige Nicodeme,Kate L. Jeffrey,Uwe Schaefer,Soren Beinke,Scott Dewell,Chun-wa Chung,Rohit Chandwani,Ivan Marazzi,Paul A. Wilson,Hervé Coste,Julia H. White,Jorge Kirilovsky,Charles M. Rice,Jose M. Lora,Rab K. Prinjha,Kevin Lee,Alexander Tarakhovsky +16 more
TL;DR: A synthetic compound (I-BET) is described that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis.
Journal ArticleDOI
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia
Mark A. Dawson,Rab K. Prinjha,Antje Dittmann,George Giotopoulos,Marcus Bantscheff,Wai-In Chan,Samuel Robson,Chun-wa Chung,Carsten Hopf,Mikhail M. Savitski,Carola Huthmacher,Emma Gudgin,Dave Lugo,Soren Beinke,Trevor D. Chapman,Emma J. Roberts,Peter Ernest Soden,Kurt R. Auger,Olivier Mirguet,Konstanze Doehner,Ruud Delwel,Alan Kenneth Burnett,Phillip Jeffrey,Gerard Drewes,Kevin Lee,Brian J. P. Huntly,Tony Kouzarides +26 more
TL;DR: It is shown that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis, establishing the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.
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