Open Access
LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions and reveal a role for LEDGF/p75 in late stage HIV-1 replication
Caroline Weydert,Belete Ayele Desimmie,Rik Schrijvers,Jonas Demeulemeester,Doortje Borrenberghs,Wannes Thys,Sofie Vets,Jelle Hendrix,Norbert Bannert,Rik Gijsbers,Frauke Christ,Jan De Rijck,Zeger Debyser +12 more
TLDR
In this article, LEDGINs are allosteric HIV integrase inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN.Abstract:
BackgroundLEDGINs are novel allosteric HIV integrase (IN) inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. They block HIV-1 integration by abrogating the interaction between LEDGF/p75 and IN as well as by allosterically inhibiting the catalytic activity of IN.ResultsHere we demonstrate that LEDGINs reduce the replication capacity of HIV particles produced in their presence. We systematically studied the molecular basis of this late effect of LEDGINs and demonstrate that HIV virions produced in their presence display a severe replication defect. Both the late effect and the previously described, early effect on integration contribute to LEDGIN antiviral activity as shown by time-of-addition, qPCR and infectivity assays. The late effect phenotype requires binding of LEDGINs to integrase without influencing proteolytic cleavage or production of viral particles. LEDGINs augment IN multimerization during virion assembly or in the released viral particles and severely hamper the infectivity of progeny virions. About 70% of the particles produced in LEDGIN-treated cells do not form a core or display aberrant empty cores with a mislocalized electron-dense ribonucleoprotein. The LEDGIN-treated virus displays defective reverse transcription and nuclear import steps in the target cells. The LEDGIN effect is possibly exerted at the level of the Pol precursor polyprotein.ConclusionOur results suggest that LEDGINs modulate IN multimerization in progeny virions and impair the formation of regular cores during the maturation step, resulting in a decreased infectivity of the viral particles in the target cells. LEDGINs thus profile as unique antivirals with combined early (integration) and late (IN assembly) effects on the HIV replication cycle.read more
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Journal ArticleDOI
Retroviral DNA Integration
TL;DR: The molecular mechanism of retroviral DNA integration is reviewed, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved, and the latest advances on anti-integrase drug development for the treatment of AIDS are discussed.
Journal ArticleDOI
Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage.
Erwann Le Rouzic,Damien Bonnard,Sophie Chasset,Jean-Michel Bruneau,Francis Chevreuil,Frédéric Le Strat,Juliette Nguyen,Roxane Beauvoir,Céline Amadori,Julie Brias,Sophie Vomscheid,Sylvia Eiler,Nicolas Levy,Olivier Delelis,Eric Deprez,Ali Saïb,Alessia Zamborlini,Stéphane Emiliani,Marc Ruff,Benoit Ledoussal,François Moreau,Richard Benarous +21 more
TL;DR: The crystal structure of Mut101 in complex with IN is determined and it is shown that the compound binds to the LEDGF-binding pocket, promoting conformational changes of IN which explain at the atomic level the allosteric effect of the IN/LEDGF interaction inhibitor on IN functions.
Journal ArticleDOI
HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis
Jacques J. Kessl,Sebla B. Kutluay,Sebla B. Kutluay,Dana Townsend,Stephanie V Rebensburg,Alison Slaughter,Ross C. Larue,Nikoloz Shkriabai,Nordine Bakouche,James R. Fuchs,Paul D. Bieniasz,Mamuka Kvaratskhelia +11 more
TL;DR: It is demonstrated that IN directly binds the viral RNA genome in virions and these interactions have specificity, as IN exhibits distinct preference for select viral RNA structural elements.
Journal ArticleDOI
A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase
Amit Sharma,Alison Slaughter,Nivedita Jena,Lei Feng,Jacques J. Kessl,Hind J. Fadel,Nirav Malani,Frances Male,Li Wu,Eric M. Poeschla,Frederic D. Bushman,James R. Fuchs,Mamuka Kvaratskhelia +12 more
TL;DR: Design of small molecules that allowed us to probe the role of HIV-1 IN multimerization independently from IN-LEDGF/p75 interactions in infected cells delineate the significance of correctly ordered IN structure for HIV- 1 particle morphogenesis and demonstrate feasibility of exploiting INMultimerization as a therapeutic target.
Journal ArticleDOI
Nuclear landscape of HIV-1 infection and integration
Marina Lusic,Robert F. Siliciano +1 more
TL;DR: In resting CD4+ T cells, the viral genome can be silenced for long periods of time, which leads to the generation of a latent reservoir of quiescent integrated HIV-1 DNA, the only nuclear event in the viral life cycle that can be pharmacologically targeted with current therapies.
References
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Journal ArticleDOI
Inhibitors of Strand Transfer That Prevent Integration and Inhibit HIV-1 Replication in Cells
Daria J. Hazuda,Peter J. Felock,Marc V. Witmer,Abigail Wolfe,Kara A. Stillmock,Jay A. Grobler,Amy S. Espeseth,Lori J. Gabryelski,William A. Schleif,Carol Blau,Michael D. Miller +10 more
TL;DR: Diketo acid inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence of their effect on integration are described.
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HIV-1 Antiretroviral Drug Therapy
Eric J. Arts,Daria J. Hazuda +1 more
TL;DR: The basic principles of antiretroviral drug therapy, the mode of drug action, and the factors leading to treatment failure are reviewed (i.e., drug resistance).
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A quantitative assay for HIV DNA integration in vivo.
TL;DR: The integration assay employs a novel quantitative form of Alu-PCR that should be generally applicable to studies of integrating viruses and gene transfer vectors and integrated proviruses.
Journal ArticleDOI
HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells
Peter Cherepanov,Goedele N. Maertens,Paul Proost,Bart Devreese,Jozef Van Beeumen,Yves Engelborghs,Erik De Clercq,Zeger Debyser +7 more
TL;DR: The findings indicate that the minimal IN molecule in human cells is a homotetramer, suggesting that at least an octamer of IN is required to accomplish coordinated integration of both retroviral long terminal repeats and that LEDGF is a cellular factor involved in this process.
Journal ArticleDOI
A role for LEDGF/p75 in targeting HIV DNA integration.
Angela Ciuffi,Manuel Llano,Eric M. Poeschla,Christian Hoffmann,Jeremy Leipzig,Paul Shinn,Joseph R. Ecker,Frederic D. Bushman +7 more
TL;DR: LEDGF is the first example of a cellular protein controlling the location of HIV integration in human cells and it is found that integration was less frequent in transcription units, lessrequent in genes regulated by LEDGF/p75 and more frequent in GC-rich DNA.