Publication

Evolution of coreceptor utilization to escape CCR5 antagonist therapy

Virology. 2016 Jul;494:198-214. doi: 10.1016/j.virol.2016.04.010. Epub 2016 Apr 26

Abstract

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.

Authors

Zhang J, Gao X, Martin J, Rosa B, Chen Z, Mitreva M, Henrich T, Kuritzkes D, Ratner L

Institute Authors

Makedonka Mitreva, Ph.D.