Exploitation of the low fidelity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the nucleotide composition bias in the HIV-1 genome to alter the drug resistance development of HIV

J Virol. 2001 Jul;75(13):5772-7. doi: 10.1128/JVI.75.13.5772-5777.2001.


The RNA genome of the lentivirus human immunodeficiency virus type 1 (HIV-1) is significantly richer in adenine nucleotides than the statistically equal distribution of the four different nucleotides that is expected. This compositional bias may be due to the guanine-to-adenine (G-->A) nucleotide hypermutation of the HIV genome, which has been explained by dCTP pool imbalances during reverse transcription. The adenine nucleotide bias together with the poor fidelity of HIV-1 reverse transcriptase markedly enhances the genetic variation of HIV and may be responsible for the rapid emergence of drug-resistant HIV-1 strains. We have now attempted to counteract the normal mutational pattern of HIV-1 in response to anti-HIV-1 drugs by altering the endogenous deoxynucleoside triphosphate pool ratios with antimetabolites in virus-infected cell cultures. We showed that administration of these antimetabolic compounds resulted in an altered drug resistance pattern due to the reversal of the predominant mutational flow of HIV (G-->A) to an adenine-to-guanine (A-->G) nucleotide pattern in the intact HIV-1-infected lymphocyte cultures. Forcing the virus to change its inherent nucleotide bias may lead to better control of viral drug resistance development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Antimetabolites / pharmacology
  • Deoxycytosine Nucleotides / metabolism
  • Drug Resistance, Microbial
  • Genome, Viral*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Spiro Compounds / pharmacology*
  • Thymidine / analogs & derivatives
  • Thymidine / pharmacology*
  • Thymine Nucleotides / metabolism
  • Uridine / analogs & derivatives


  • Anti-HIV Agents
  • Antimetabolites
  • Deoxycytosine Nucleotides
  • Reverse Transcriptase Inhibitors
  • Spiro Compounds
  • Thymine Nucleotides
  • 1-(2',5'-bis-O-(tert-butyldimethylsilylribofuranosyl)-3-N-methylthymine)-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide)
  • 2'-deoxycytidine 5'-triphosphate
  • HIV Reverse Transcriptase
  • thymidine 5'-triphosphate
  • Thymidine
  • TSAO-T
  • Uridine