Development of mutations in HIV-1 PR hinders the activity of antiretroviral drugs, forcing changes in drug prescription. Most resistance assessments used to date rely on expert-based rules on predefined sets of stereotypical mutations; such information-driven approach cannot capture new polymorphisms nor be applied for new drugs. Computational modeling could provide a more general assessment of drug resistance, and could be made available to clinicians through the Internet. We have created a protocol involving sequence comparison and all-atom protein-ligand induced fit simulations to predict resistance at the molecular level. We first compared our predictions with experimentally determined IC50 of darunavir, amprenavir, ritonavir and indinavir from reference PR mutants displaying different resistance levels. We then performed analyses on a large set of variants harboring more than 10 mutations. Finally, several sequences from real patients were analyzed for amprenavir and darunavir. Our computational approach detected all genotype changes triggering high-level resistance, even those involving a large number of mutations.

The authors thank Mark D. Shenderovich for providing data and helpful discussion. Computational resources were provided by the Barcelona Supercomputing Center. This work was supported by the Spanish MINECO (BIO2012-32868 and CTQ2013-48287) and the Severo Ochoa Program (R.S.). MO is an ICREA Academia Researcher.

Peer Reviewed