Evolution of the human immunodeficiency virus type 1 envelope during infection reveals molecular corollaries of specificity for coreceptor utilization and AIDS pathogenesis

The evolution of human immunodeficiency virus type 1 infection is associate d with a shift in the target cell population, driven by variability in core ceptor utilization resulting from diversity in env. To elucidate the potent ial consequences of these changes for Env-mediated fusion over the course o f AIDS, we examined the biological properties of serial viral isolates and determined coreceptor utilization by the products of env cloned from two in dividuals, followed from the detection of seroconversion throughout the cou rse of their infection. One had a typical course, and the other had an acce lerated progression. Early isolates were non-syncytium inducing, and the co rresponding Env exclusively utilized CCR5, whereas Env from late phases of infection showed restricted utilization of CXCR4 in both patients. Env from subject SC24, who had a standard progression, demonstrated multitropism, m anifested by utilization of CCR3, CXCR4, and CCR5 in the intervening period . In contrast, Env from patient SC51, who experienced early conversion to t he syncytium-inducing phenotype, developed dualtropic coreceptor utilizatio n of CCR5 and CXCR4. Genetic analysis of env from each isolate revealed tha t those with an X4 phenotype formed a distinct subcluster within each subje ct. Analysis of chimeras constructed from R5 and multispecific env from pat ient SC24 demonstrated that while the V3 domain played a dominant role in d etermining coreceptor utilization, sequences in the V4-V5 region also contr ibuted to the latter phenotype. Immunoprecipitation experiments confirmed t hat the hybrid Env proteins were expressed at similar levels. These experim ents demonstrate that progression from the R5 to X4 phenotype may occur thr ough a multi- or dual-tropic intermediate and that multiple domains contrib ute to this process.