Contingency and Entrenchment of Drug-Resistance Mutations in HIV Viral Proteins.

The ability of HIV-1 to rapidly mutate leads to antiretroviral therapy (ART) failure among infected patients. Drug-resistance mutations (DRMs), which cause a fitness penalty to intrinsic viral fitness, are compensated by accessory mutations with favorable epistatic interactions which cause an evolutionary trapping effect, but the kinetics of this overall process has not been well characterized. Here, using a Potts Hamiltonian model describing epistasis combined with kinetic Monte Carlo simulations of evolutionary trajectories, we explore how epistasis modulates the evolutionary dynamics of HIV DRMs. We show how the occurrence of a drug-resistance mutation is contingent on favorable epistatic interactions with many other residues of the sequence background and that subsequent mutations entrench DRMs. We measure the time-autocorrelation of fluctuations in the likelihood of DRMs due to epistatic coupling with the sequence background, which reveals the presence of two evolutionary processes controlling DRM kinetics with two distinct time scales. Further analysis of waiting times for the evolutionary trapping effect to reverse reveals that the sequences which entrench (trap) a DRM are responsible for the slower time scale. We also quantify the overall strength of epistatic effects on the evolutionary kinetics for different mutations and show these are much larger for DRM positions than polymorphic positions, and we also show that trapping of a DRM is often caused by the collective effect of many accessory mutations, rather than a few strongly coupled ones, suggesting the importance of multiresidue sequence variations in HIV evolution. The analysis presented here provides a framework to explore the kinetic pathways through which viral proteins like HIV evolve under drug-selection pressure.