HIV-1 can escape from RNA interference by evolving an alternative structure in its RNA genome

Nucleic Acids Res. 2005 Feb 1;33(2):796-804. doi: 10.1093/nar/gki220. Print 2005.


HIV-1 replication can be efficiently inhibited by intracellular expression of an siRNA targeting the viral RNA. However, HIV-1 escape variants emerged after prolonged culturing. These RNAi-resistant viruses contain nucleotide substitutions or deletions in or near the targeted sequence. We observed an inverse correlation between the level of resistance and the stability of the siRNA/target-RNA duplex. However, two escape variants showed a higher level of resistance than expected based on the duplex stability. We demonstrate that these mutations induce alternative folding of the RNA such that the target sequence is occluded from binding to the siRNA, resulting in reduced RNAi efficiency. HIV-1 can thus escape from RNAi-mediated inhibition not only through nucleotide substitutions or deletions in the siRNA target sequence, but also through mutations that alter the local RNA secondary structure. The results highlight the enormous genetic flexibility of HIV-1 and provide detailed molecular insight into the sequence specificity of RNAi and the impact of target RNA secondary structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • Base Sequence
  • Cell Line
  • Gene Products, nef / antagonists & inhibitors
  • Gene Products, nef / genetics
  • Genome, Viral
  • HIV-1 / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Nucleic Acid Conformation
  • RNA Interference*
  • RNA Stability
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology*
  • RNA, Viral / chemistry*
  • RNA, Viral / drug effects
  • RNA, Viral / genetics
  • nef Gene Products, Human Immunodeficiency Virus


  • Anti-HIV Agents
  • Gene Products, nef
  • RNA, Small Interfering
  • RNA, Viral
  • nef Gene Products, Human Immunodeficiency Virus