ABSTRACT
Like all other retroviruses, human immunodeficiency virus type 1 (HIV-1) contains the multifunctional enzyme reverse transcriptase (RT). HIV-1 RT is essential for the conversion of singlestranded viral RNA into a linear double-stranded DNA that is subsequently integrated into the host cell chromosomes. Three-dimensional crystal structures of HIV-1 RT have been determined both for the unliganded form of the protein and for complexes with either templateprimer substrate or nonnucleoside inhibitors. A viable drug-resistant RT mutant should be able to recognize normal nucleoside triphosphate, yet reject a nucleoside analog. However, there is a good chance that drug resistance could result from mutations in HIV-1 RT that influence the precise positioning of template-primer. In addition, drug-resistant variants of HIV-1 RT emerge rapidly in the presence of most inhibitors. Systematic analysis of wildtype and drug-resistant mutant HIV-1 RT structures in complexes with various nonnucleoside RT inhibitors (NNRTIs) should provide additional insights about constraints that could be used to optimize the design of NNRTIs.
