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

Retrovirology. 2015 Feb 12:12:16. doi: 10.1186/s12977-014-0134-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • HIV Protease / metabolism
  • HIV-1 / physiology*
  • Host-Pathogen Interactions*
  • Humans
  • Proteolysis
  • Transcription Factors / metabolism*
  • Virus Integration*
  • Virus Replication*
  • pol Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • PSIP1 protein, human
  • Transcription Factors
  • pol Gene Products, Human Immunodeficiency Virus
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1