HIV-1 IN/Pol recruits LEDGF/p75 into viral particles

Retrovirology

Zeger Debyser²  Frauke Christ²  Rik Gijsbers²  Norbert Bannert¹  Jan Mast⁴  Jan De Rijck²  Igor Paron⁵  Paul Proost⁶  Jonas Demeulemeester²  Sofie Vets²  Rik Schrijvers²  Caroline Weydert²  Belete Ayele Desimmie³ 

[1] Robert Koch Institute, Centre for HIV and Retrovirology, Berlin, Germany;Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Laboratory for Molecular Virology and Gene Therapy, Leuven, Flanders, Belgium;Present address: Viral Mutation Section, HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA;Veterinary and Agrochemical Research Centre CODA-CERVA, Brussels, Belgium;Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, D-82152, Germany;KU Leuven, Laboratory of Molecular Immunology, Rega Institute, Leuven, Flanders, Belgium

关键词: Assembly;    Protease cleavage sites;    Protease;    LEDGF/p75;    Integrase;   

Others  :  1162857
DOI  :  10.1186/s12977-014-0134-4

 received in 2014-10-10, accepted in 2014-12-22,  发布年份 2015

【 摘 要 】

Background

The dynamic interaction between HIV and its host governs the replication of the virus and the study of the virus-host interplay is key to understand the viral lifecycle. The host factor lens epithelium-derived growth factor (LEDGF/p75) tethers the HIV preintegration complex to the chromatin through a direct interaction with integrase (IN). Small molecules that bind the LEDGF/p75 binding pocket of the HIV IN dimer (LEDGINs) block HIV replication through a multimodal mechanism impacting early and late stage replication including HIV maturation. Furthermore, LEDGF/p75 has been identified as a Pol interaction partner. This raised the question whether LEDGF/p75 besides acting as a molecular tether in the target cell, also affects late steps of HIV replication.

Results

LEDGF/p75 is recruited into HIV-1 particles through direct interaction with the viral IN (or Pol polyprotein) and is a substrate for HIV-1 protease. Incubation in the presence of HIV-1 protease inhibitors resulted in detection of full-length LEDGF/p75 in purified viral particles. We also demonstrate that inhibition of LEDGF/p75-IN interaction by specific mutants or LEDGINs precludes incorporation of LEDGF/p75 in virions, underscoring the specificity of the uptake. LEDGF/p75 depletion did however not result in altered LEDGIN potency.

Conclusion

Together, these results provide evidence for an IN/Pol mediated uptake of LEDGF/p75 in viral particles and a specific cleavage by HIV protease. Understanding of the possible role of LEDGF/p75 or its cleavage fragments in the viral particle awaits further experimentation.

【 授权许可】

   
2015 Desimmie et al.; licensee BioMed Central.

【 图 表 】

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