Epistasis and entrenchment of drug resistance in HIV-1 subtype B

The development of drug resistance in HIV is the result of primary mutations whose effects on viral fitness depend on the entire genetic background, a phenomenon called 'epistasis'. Based on protein sequences derived from drug-experienced patients in the Stanford HIV database, we use a co-evolutionary (Potts) Hamiltonian model to provide direct confirmation of epistasis involving many simultaneous mutations. Building on earlier work, we show that primary mutations leading to drug resistance can become highly favored (or entrenched) by the complex mutation patterns arising in response to drug therapy despite being disfavored in the wild-type background, and provide the first confirmation of entrenchment for all three drug-target proteins: protease, reverse transcriptase, and integrase; a comparative analysis reveals that NNRTI-induced mutations behave differently from the others. We further show that the likelihood of resistance mutations can vary widely in patient populations, and from the population average compared to specific molecular clones.