Structural and biochemical effects of human immunodeficiency virus mutants resistant to non-nucleoside reverse transcriptase inhibitors

Abstract

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.