Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6138459 | Virology | 2016 | 17 Pages |
â¢Novel integrative approach combines phenotypic and genotypic HIV-1 tropism analysis.â¢Phenotypically validated full-length gp160 sequences are examined with confidence.â¢Findings confirmed previously published tropism determinants in the V3 region.â¢New regions of interests include gp120-gp41 and gp41-gp41 interaction surfaces.â¢Potentially global mechanisms are implicated in modulating coreceptor specificity.
The HIV-1 envelope interacts with coreceptors CCR5 and CXCR4 in a dynamic, multi-step process, its molecular details not clearly delineated. Use of CCR5 antagonists results in tropism shift and therapeutic failure. Here we describe a novel approach using full-length patient-derived gp160 quasispecies libraries cloned into HIV-1 molecular clones, their separation based on phenotypic tropism in vitro, and deep sequencing of the resultant variants for structure-function analyses. Analysis of functionally validated envelope sequences from patients who failed CCR5 antagonist therapy revealed determinants strongly associated with coreceptor specificity, especially at the gp120-gp41 and gp41-gp41 interaction surfaces that invite future research on the roles of subunit interaction and envelope trimer stability in coreceptor usage. This study identifies important structure-function relationships in HIV-1 envelope, and demonstrates proof of concept for a new integrated analysis method that facilitates laboratory discovery of resistant mutants to aid in development of other therapeutic agents.
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