LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions

Retrovirology

Zeger Debyser¹  Frauke Christ¹  Rik Gijsbers¹  Norbert Bannert³  Jelle Hendrix²  Jan De Rijck¹  Johan Hofkens²  Barbara Van Remoortel¹  Sofie Vets¹  Wannes Thys¹  Caroline Weydert¹  Doortje Borrenberghs²  Jonas Demeulemeester¹  Rik Schrijvers¹  Belete Ayele Desimmie¹ 

[1] Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Kapucijnenvoer 33, Leuven, Flanders, 3000, Belgium;Laboratory for Photochemistry and Spectroscopy, KU Leuven, Celestijnenlaan 200F, Heverlee, Flanders, 3001, Belgium;Robert Koch Institute, Centre for HIV and Retrovirology, Nordufer 20, Berlin, 13353, Germany

关键词: LEDGINs;    Integrase multimerization;    Integrase;    HIV replication;    Antivirals;   

Others  :  1209120
DOI  :  10.1186/1742-4690-10-57

 received in 2013-03-15, accepted in 2013-05-07,  发布年份 2013

【 摘 要 】

Background

LEDGINs 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.

Results

Here 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.

Conclusion

Our 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.

【 授权许可】

   
2013 Desimmie et al.; licensee BioMed Central Ltd.

【 图 表 】

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