Covariation of Mutations in the V3 Loop of HIV-1: An Information Theoretic Analysis

The V3 loop of the Human Immunodeficiency Virus Type-1 (HIV-1) envelope protein is a highly variable region that is both functionally and immunologically important. We have used an information theoretic quantity called mutual information, a measure of covariation, to quantify dependence between mutations in the loop using available amino acid sequences from the V3 region. Certain pairs of sites, including non-contiguous sites along the sequence, do not have independent mutations, but display considerable, statistically significant, co-varying mutations as measured by mutual information. Such interdependence may have implications for structural or functional relationships between sites; separate experimental evidence indicates functional linkage between some of the pairs of sites with high mutual information. Further specific mutational studies are suggested by our analysis. The methods used are generally applicable to the study of variable proteins.