Changing selection on amino acid substitutions in Gag protein between major HIV-1 subtypes

Amino acid preferences at a protein site depend on the role of this site in protein function and structure as well as on external constraints. All these factors can change in the course of evolution, making amino acid propensities of a site time-dependent. When viral subtypes divergently evolve in different host subpopulations, such changes may depend on genetic, medical and socio-cultural differences between these subpopulations. Here, using our previously developed phylogenetic approach, we describe 69 amino acid sites of the Gag protein of HIV-1 where amino acids have different impact on viral fitness in six major subtypes of the type M. These changes in preferences trigger adaptive evolution; indeed, 32 (46%) of these sites experienced strong positive selection at least in one of the subtypes. At some of the sites, changes in amino acid preferences may be associated with differences in immune escape between subtypes. The prevalence of different amino acids within a subtype is only a poor predictor for whether it is preferred in this subtype according to the phylogenetic analysis. Therefore, attempts to identify the factors of viral evolution from comparative genomics data should integrate across multiple sources of information.