Structural and biochemical effects of human immunodeficiency virus mutants resistant to non-nucleoside reverse transcriptase inhibitors.
Non-nucleoside reverse transcriptase inhibitors are potent, highly specific, noncompetitive inhibitors of the Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. They are used commonly as part of potent antiretroviral regimens for the treatment of HIV-1 infection, either in combination with nucleoside analogs, protease inhibitors, or both. A major limitation to the success of non-nucleoside inhibitors is the rapid emergence of HIV-1 variants resistant to these drugs. These drug-resistant variants contain one or more mutations in the non-nucleoside inhibitor binding pocket of reverse transcriptase. This review summarizes the effects that these mutations have on non-nucleoside inhibitor binding, reverse transcriptase structure, HIV-1 replication, and the ability of reverse transcriptase to catalyze DNA polymerization and RNase H cleavage. In addition, studies are summarized evaluating important interactions between mutations conferring resistance to non-nucleoside inhibitors and those conferring resistance to nucleoside analogs. The studies summarized in this review provide important insights into potentially useful approaches to minimize the development of HIV-1 resistant to non-nucleoside inhibitors.
Domaoal
Robert A
RA
Department of Medicine, University of Rochester School of Medicine and Dentistry, NY 14642, USA
Demeter
Lisa M
LM
D003062:Codon; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
D003062:Codon; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase