Decoding HIV resistance: from genotype to therapy

Abstract

Genetic variation in HIV poses a major challenge for prevention and treatment of the AIDS pandemic. Resistance occurs by mutations in the target proteins that lower affinity for the drug or alter the protein dynamics, thereby enabling viral replication in the presence of the drug. Due to the prevalence of drug-resistant strains, monitoring the genotype of the infecting virus is recommended. Computational approaches for predicting resistance from genotype data and guiding therapy are discussed. Many prediction methods rely on rules derived from known resistance-associated mutations, however, statistical or machine learning can improve the classification accuracy and assess unknown mutations. Adding classifiers such as information on the atomic structure of the protein can further enhance the predictions.

Keywords: HIV/AIDS; antiretroviral therapy; drug resistance mutations; genotype interpretation; integrase strand transfer inhibitor; non-nucleoside reverse transcriptase inhibitor; nucleoside reverse transcriptase inhibitor; protease inhibitor; supervised machine learning.

Figure 1.. Reverse transcriptase structure and sites of resistant mutations.

Locations of resistance-associated mutations mapped on the heterodimer of HIV reverse transcriptase in complex with NNRTI lersivirine (PDB: 2WOM). (A) Heterodimer of reverse transcriptase. The two subunits are shown as light gray and dark gray ribbons with NNRTI in black bonds. Sites of mutations associated with resistance to NRTIs are indicated by dark gray spheres on the left subunit. Mutations associated with NNRTI resistance are shown on the right in light gray [20]. (B) Expanded NNRTI binding site with mutations labeled. (C) Expanded region in left subunit with sites of mutations associated with NRTIs labeled. NNRTI: Non-nucleoside RT inhibitor; NRTI: Nucleoside RT inhibitor; TAM: Thymidine analog-associated mutation.

Figure 2.. Protease dimer showing sites of resistance mutations.

(A) Major and minor mutations associated with resistance. Locations of resistance-associated mutations mapped on the HIV protease dimer bound with DRV (PDB: 2IEN). The protease dimer is shown in ribbons with DRV in black sticks. Sites of mutations associated with drug resistance [20] are indicated by spheres. Mutations altering inhibitor binding are in dark gray and mutations affecting dimer stability or flap dynamics are indicated in light gray on the left subunit. Distal mutations with poorly defined effects are shown in gray on the right subunit. DRV: Darunavir.

Figure 3.. Catalytic core domain of HIV integrase with sites of resistance mutations.

Locations of resistance mutations mapped onto the catalytic core domain of HIV integrase (PDB: 1QS4). The core domain is shown as ribbons with inhibitor in black sticks. Sites of mutations are indicated by spheres with light gray for major mutations and dark gray for minor or accessory mutations.

Figure 4.. Delauney triangulation of HIV protease.

Graph constructed from the crystal structure of HIV protease as described in [76].