Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs).
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.
Sluis-Cremer
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Lady Davis Institute for Medical Research and McGill University AIDS Centre, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Arion
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Parniak
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D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects*; D009705:Nucleosides / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors