EVOLUTION OF ENVELOPE SEQUENCES FROM THE GENITAL-TRACT AND PERIPHERAL-BLOOD OF WOMEN INFECTED WITH CLADE-A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

The development of viral diversity during the course of human immunode ficiency virus type 1 (HIV-1) infection may significantly influence vi ral pathogenesis. The paradigm for HIV-1 evolution is based primarily on studies of male cohorts in which individuals were presumably infect ed with a single virus variant of subtype B HIV-1. In this study, we e valuated virus evolution based on sequence information of the V1, V2, and V3 portions of HIV-1 clade A envelope genes obtained from peripher al blood and cervical secretions of three women with genetically heter ogeneous viral populations near seroconversion. At the first sample fo llowing seroconversion, the number of nonsynonymous substitutions per potential nonsynonymous site (dn) significantly exceeded substitutions at potential synonymous sites (ds) in plasma viral sequences from all individuals. Generally, values of dn remained higher than values of d s as sequences from blood or mucosa evolved. Mutations affected each o f the three variable regions of the envelope gene differently; inserti ons and deletions dominated changes in V1, substitutions involving cha rged amino acids occurred in V2, and sequential replacement of amino a cids over time at a small subset of positions distinguished V3. The re lationship among envelope nucleotide sequences obtained from periphera l blood mononuclear cells, plasma, and cervical secretions was evaluat ed for each individual by both phylogenetic and phenetic analyses. In all subjects, sequences from within each tissue compartment were more closely related to each other than to sequences from other tissues (ph ylogenetic tissue compartmentalization). At time points after seroconv ersion in two individuals, there was also greater genetic identity amo ng sequences from the same tissue compartment than among sequences fro m different tissue compartments (phenetic tissue compartmentalization) . Over time, temporal phylogenetic and phenetic structure was detectab le in mucosal and plasma viral samples from all three women, suggestin g a continual process of migration of one or a few infected cells into each compartment followed by localized expansion and evolution of tha t population.