Entrenchment and evolution of drug resistance in HIV

Abstract

The rapid evolution of HIV is constrained by epistatic interactions between mutations in its fitness landscape. Multiple sequence alignments (MSAs) of related protein sequences carry a wealth of information that can be used to build coevolutionary models of protein structure and fitness. Based on protein sequences derived from HIV patients, we use a coevolutionary (Potts) Hamiltonian model to show that primary mutations leading to drug resistance in HIV, can become highly advantageous or ‘entrenched’ in specific sequence backgrounds, despite generally detrimental effects in the wild-type virus.