Genotypic testing for human immunodeficiency virus type 1 drug resistance

Abstract

There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs.

FIG. 1.

Structural model of HIV-1 protease homodimer labeled with protease inhibitor resistance mutations. The polypeptide backbone of both protease subunits (positions 1 to 99) is shown. The active site, made up of positions 25 to 27 from both subunits, is displayed in ball and stick mode. The protease inhibitor resistance mutations are shown for the subunit on the left but not for the subunit on the right. The protease was cocrystallized with indinavir, which is displayed in space-fill mode. This drawing is based on a structure published by Chen et al. (46).

FIG. 2.

Structural model of HIV-1 RT labeled with NRTI resistance mutations. The polypeptide backbone of the fingers and palm domain (positions 1 to 235) and DNA primer and template strands are shown. The active-site positions (110, 185, and 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. (158) and are shown in front (A) and back (B) views.

FIG. 3.

Structural model of HIV-1 RT labeled with NNRTI resistance mutations. The polypeptide backbone of the complete p66 subunit (positions 1 to 560) and DNA primer and template strands are shown. This drawing is based on the structure published by Kohlstaedt et al. (199) in which the RT is cocrystallized 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.