Adaptive HIV-1 evolutionary trajectories are constrained by protein stability

Abstract

Despite the use of combination antiretroviral drugs for the treatment of HIV-1 infection, the emergence of drug resistance remains a problem. Resistancemay be conferred either by a singlemutation or a concerted set ofmutations. The involvement ofmultiplemutations can arise due to interactions between sites in the amino acid sequence as a consequence of the need to maintain protein structure. To better understand the nature of such epistatic interactions, we reconstructed the ancestral sequences of HIV-1's Pol protein, and traced the evolutionary trajectories leading tomutations associated with drug resistance. Using contemporary and ancestral sequences wemodelled the effects ofmutations (i.e. amino acid replacements) on protein structure to understand the functional effects of residue changes. Although themajority of resistance-associated sequences tend to destabilise the protein structure, we find there is a general tendency for protein stability to decrease across HIV-1's evolutionary history. That a similar pattern is observed in the non-drug resistance lineages indicates that non-resistantmutations, for example, associated with escape fromthe immune response, also impacts on protein stability. Maintenance of optimal protein structure therefore represents amajor constraining factor to the evolution of HIV-1.