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

Nucleoside reverse transcriptase inhibitors (NRTIs), such as 3'-azido-3'-de oxythymidine, 2',3'-dideoxyinosine and 2',3'-dideoxy-3'-thiacytidine, are e ffective inhibitors of human immunodeficiency type 1 (HIV-I) replication. N RTIs 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-I reverse transcriptase (RT), further viral DNA synthesis is effectively terminated. NRTIs should therefore represent the ideal anti viral agent. Unfortunately, HIV-I inevitably develops resistance to these i nhibitors, and this resistance correlates with mutations in RT. To date, th ree phenotypic mechanisms have been identified or proposed to account for H IV-1 RT resistance to NRTIs. These mechanisms include alterations of RT dis crimination between NRTIs and the analogous dNTP (direct effects on NRTI bi nding and/or incorporation), alterations in RT-template/primer interactions . which may influence subsequent NRTI incorporation, and enhanced removal o f the chain-terminating residue from the 3' end of the primer. These differ ent resistance phenotypes seem to correlate with different sets of mutation s in RT. This review discusses the relationship between HIV-I drug resistan ce genotype and phenotype, in relation to our current knowledge of HIV-1 RT structure.