Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration

Chem Biol. 2015 Jun 18;22(6):712-23. doi: 10.1016/j.chembiol.2015.04.020. Epub 2015 Jun 4.

Abstract

The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both in vitro and in vivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, in vitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / chemistry
  • 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / metabolism
  • 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
  • Aptamers, Nucleotide / chemistry
  • Aptamers, Nucleotide / metabolism
  • Benzamides / chemistry
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • DNA / chemistry
  • DNA / metabolism
  • DNA Repair
  • Gene Expression / drug effects
  • HEK293 Cells
  • HIV-1 / physiology*
  • Humans
  • Morpholines / chemistry
  • Morpholines / metabolism
  • Morpholines / pharmacology
  • Protein Binding
  • Pyrroles / chemistry
  • Pyrroles / metabolism
  • Pyrroles / pharmacology
  • Rad51 Recombinase / chemistry
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism*
  • Stilbenes / chemistry
  • Stilbenes / metabolism
  • Stilbenes / pharmacology
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology
  • Virus Internalization / drug effects
  • Virus Replication / drug effects

Substances

  • 3-((benzylamino)sulfonyl)-4-bromo-N-(4-bromophenyl)benzamide
  • 3-chloro-1-(3,4-dichlorophenyl)-4-(4-morpholinyl)-1H-pyrrole-2,5-dione
  • Aptamers, Nucleotide
  • Benzamides
  • Morpholines
  • Pyrroles
  • Stilbenes
  • Sulfonamides
  • pterostilbene
  • DNA
  • RAD51 protein, human
  • Rad51 Recombinase
  • 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid