A model for alignment of Env V1 and V2 hypervariable domains from human and simian immunodeficiency viruses

HIV-1 env gene encodes a multifunctional glycoprotein that is involved in virus infectivity, interactions between the virus and the host immune system, and phenotypic characteristics of virus isolates in culture. A number of Env functions map by genetic analysis to V3, one of five hypervariable domains that compose the surface component of Env gp120. V1 and V2 hypervariable domains of Env also contribute to the phenotype of HIV-1, although relationships between V1 and V2 genotypes and biological characteristics of HIV-1 are not well defined. One limitation to genetic analysis of V1 and V2 is the extensive length variation that results from in-frame deletions or duplications of nucleotides and renders alignments difficult among V1 and V2 sequences from different populations of viruses. We developed a model to facilitate rational alignments of V1 and V2 domains independent of their length. The alignment strategy constrains gap placement in V1 and V2 so that glycan modification motifs and potential alpha helices are intact. The alignment model accommodates the spectrum of HIV-1 subtypes, as well as HIV-2 and SIV V1 and V2 sequences. The model will facilitate genetic analysis and interpretation of amino acid changes in the hypervariable domains. For example, charged and uncharged amino acids are conserved in defined positions in each of the V1 and V2 hypervariable domains from a subset of HIV-1 subtype B isolates. Biochemical characteristics of amino acids in V1 and V2 appear unrelated to cytotropic or syncytium-inducing phenotypes of the viruses.