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Evolution of coreceptor utilization to escape CCR5 antagonist therapy

Authors :
Daniel R. Kuritzkes
Xiang Gao
Jie Zhang
John Martin
Bruce A. Rosa
Zheng Chen
Lee Ratner
Timothy J. Henrich
Makedonka Mitreva
Source :
Virology
Publisher :
The Authors. Published by Elsevier Inc.

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.

Details

Language :
English
ISSN :
00426822
Database :
OpenAIRE
Journal :
Virology
Accession number :
edsair.doi.dedup.....9cb21cd0f2579f8e309d90c47b5224e6
Full Text :
https://doi.org/10.1016/j.virol.2016.04.010