Zhang, JieGao, XiangMartin, JohnRosa, BruceChen, ZhengMitreva, MakedonkaHenrich, Timothy J.Kuritzkes, DanielRatner, Lee2016-08-092016Zhang, Jie, Xiang Gao, John Martin, Bruce Rosa, Zheng Chen, Makedonka Mitreva, Timothy Henrich, Daniel Kuritzkes, and Lee Ratner. 2016. “Evolution of coreceptor utilization to escape CCR5 antagonist therapy.” Virology 494 (1): 198-214. doi:10.1016/j.virol.2016.04.010. http://dx.doi.org/10.1016/j.virol.2016.04.010.0042-6822http://nrs.harvard.edu/urn-3:HUL.InstRepos:27822165The 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.en-USHIV/AIDSTropism shiftCoreceptor inhibitorDrug resistanceJournal Article2016-08-0910.1016/j.virol.2016.04.010