Before revision:  We analyze the "fossils" of the evolutionary trajectories of a protein contained in the sequence data, and show that epistatic interactions continue to enrich in the HIV-1 protease as more potent drugs enter the market. While initially epistatic interactions are likely to constrain the evolvability of a protein, we find no evidence that the HIV-1 protease has reached its potential for adaptation after 9 years of adapting to a changing drug environment .
After revision:  We analyze the "fossils" of the evolutionary trajectories of a protein contained in the sequence data, and show that epistasis continues to enrich under strong selection, but not for proteins whose environment is unchanged. The increase in epistasis compensates for the information loss due to sequence variability brought about by treatment, and facilitates adaptation in the increasingly rugged fitness landscape of treatment. While epistasis is thought to enhance evolvability via valley-crossing early-on in adaptation, it can hinder adaptation later when the landscape has turned rugged. However, we find no evidence that the HIV-1 protease has reached its potential for adaptation after 9 years of adapting to a changing drug environment .