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Evolution of coreceptor utilization to escape CCR5 antagonist therapy
- 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.
- Subjects :
- Models, Molecular
0301 basic medicine
Receptors, CXCR4
Receptors, CCR5
Anti-HIV Agents
Protein Conformation
viruses
HIV Infections
Viral quasispecies
CCR5 receptor antagonist
HIV Envelope Protein gp120
Biology
Polymorphism, Single Nucleotide
Article
Deep sequencing
Cell Line
Evolution, Molecular
Structure-Activity Relationship
03 medical and health sciences
Protein structure
Gene Frequency
Virology
Humans
Position-Specific Scoring Matrices
Structure–activity relationship
Amino Acid Sequence
Alleles
Phylogeny
Tropism
Tropism shift
Genetics
Coreceptor inhibitor
env Gene Products, Human Immunodeficiency Virus
High-Throughput Nucleotide Sequencing
virus diseases
Phenotype
Peptide Fragments
3. Good health
Viral Tropism
030104 developmental biology
Drug resistance
CCR5 Receptor Antagonists
HIV-1
Tissue tropism
RNA, Viral
HIV/AIDS
Subjects
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