Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs)

Cell Mol Life Sci. 2000 Sep;57(10):1408-22. doi: 10.1007/PL00000626.


Nucleoside reverse transcriptase inhibitors (NRTIs), such as 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine and 2',3'-dideoxy-3'-thiacytidine, are effective inhibitors of human immunodeficiency type 1 (HIV-1) replication. NRTIs are deoxynucleoside triphosphate analogs, but lack a free 3'-hydroxyl group. Once NRTIs are incorporated into the nascent viral DNA, in reactions catalyzed by HIV-1 reverse transcriptase (RT), further viral DNA synthesis is effectively terminated. NRTIs should therefore represent the ideal antiviral agent. Unfortunately, HIV-1 inevitably develops resistance to these inhibitors, and this resistance correlates with mutations in RT. To date, three phenotypic mechanisms have been identified or proposed to account for HIV-1 RT resistance to NRTIs. These mechanisms include alterations of RT discrimination between NRTIs and the analogous dNTP (direct effects on NRTI binding and/or incorporation), alterations in RT-template/primer interactions, which may influence subsequent NRTI incorporation, and enhanced removal of the chain-terminating residue from the 3' end of the primer. These different resistance phenotypes seem to correlate with different sets of mutations in RT. This review discusses the relationship between HIV-1 drug resistance genotype and phenotype, in relation to our current knowledge of HIV-1 RT structure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Drug Resistance, Microbial
  • HIV-1 / drug effects*
  • Nucleosides / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*


  • Anti-HIV Agents
  • Nucleosides
  • Reverse Transcriptase Inhibitors