The Genetic Basis of HIV-1 Resistance to Reverse Transcriptase and Protease Inhibitors

Abstract

HIV-1 drug resistance is caused by mutations in the reverse transcriptase (RT) and protease enzymes, the molecular targets of antiretroviral therapy. At the beginning of the year 2000, two expert panels recommended that HIV-1 RT and protease susceptibility testing be used to help select antiretroviral drugs for HIV-1-infected patients. Genotypic assays have been developed to detect HIV-1 mutations known to confer antiretroviral drug resistance. Genotypic assays using dideoxynucleoside sequencing provide extensive insight into the presence of drug-resistant variants in the population of viruses within an individual. However, the interpretation of these assays in clinical settings is formidable because of the large numbers of drug resistance mutations and because these mutations interact with one another and emerge in complex patterns. In addition, cross-resistance between antiretroviral drugs is greater than that anticipated from initial in vitro studies. This review summarises the published data linking HIV-1 RT and protease mutations to in vitro and clinical resistance to the currently available nucleoside RT inhibitors, non-nucleoside RT inhibitors, and protease inhibitors.

Fig. 1

Structural model of HIV-1 reverse transcriptase (RT) labelled with nucleoside RT inhibitor (NRTI) resistance mutations. The polypeptide backbone of the fingers and palm domain (positions 1-235), and DNA primer and template strands are shown. The active site positions (110, 185, 186) are displayed in ball-and-stick mode. The incoming nucleotide is displayed in space-fill mode. These drawings are based on the structure published by Huang et al. and are shown in «front»(a) and «back» (b) views.

Fig. 2

Structural model of HIV-1 reverse transcriptase (RT) labelled with non-nucleoside RT inhibitor (NNRTI) resistance mutations. The polypeptide backbone of the complete p66 subunit (positions 1-560), and DNA primer and template strands are shown. This drawing is based on the structure provided by Kohlstaedt et al. in which the RT is co-crystallised with nevirapine, which is displayed in space-fill mode. The positions associated with NNRTI resistance are shown surrounding the hydrophobic pocket to which nevirapine and other NNRTIs bind.

Fig. 3

Structural model of HIV-1 protease homodimer labelled with protease inhibitor resistance mutations. The polypeptide backbone of both protease subunits (positions 1-99) is shown. The active site (positions 25-27) is displayed in ball-and-stick mode. The protease was co-crystallised with a protease inhibitor, which is displayed in space-fill mode.