Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations

J Biol Chem. 2004 Jan 2;279(1):509-16. doi: 10.1074/jbc.M308806200. Epub 2003 Oct 9.


HIV-1 drug resistance mutations are often inversely correlated with viral fitness, which remains poorly described at the molecular level. Some resistance mutations can also suppress resistance caused by other resistance mutations. We report the molecular mechanisms by which a virus resistant to lamivudine with the M184V reverse transcriptase mutation shows increased susceptibility to tenofovir and can suppress the effects of the tenofovir resistance mutation K65R. Additionally, we report how the decreased viral replication capacity of resistant viruses is directly linked to their decreased ability to use natural nucleotide substrates and that combination of the K65R and M184V resistance mutations leads to greater decreases in viral replication capacity. All together, these results define at the molecular level how nucleoside-resistant viruses can be driven to reduced viral fitness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Amino Acid Substitution
  • Anti-HIV Agents / classification
  • Anti-HIV Agents / pharmacology*
  • Binding Sites
  • Drug Resistance, Viral
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Organophosphonates*
  • Organophosphorus Compounds / pharmacology
  • Phenotype
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Tenofovir
  • Zidovudine / pharmacology


  • Anti-HIV Agents
  • Organophosphonates
  • Organophosphorus Compounds
  • Recombinant Proteins
  • Zidovudine
  • Tenofovir
  • HIV Reverse Transcriptase
  • Adenine