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Evolution of CCR5 Antagonist Resistance in an HIV-1 Subtype C Clinical Isolate
- Source :
- JAIDS Journal of Acquired Immune Deficiency Syndromes. 55:420-427
- Publication Year :
- 2010
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2010.
-
Abstract
- Objectives: We previously reported vicriviroc (VCV) resistance in an HIV-infected subject and used deep sequencing and clonal analyses to track the evolution of V3 sequence forms over 28 weeks of therapy. Here, we test the contribution of gp120 mutations to CCR5 antagonist resistance and investigate why certain minority V3 variants emerged as the dominant species under drug pressure. Methods: Nineteen site-directed HIV-1 mutants were generated that contained gp120 VCV resistance mutations. Viral sensitivities to VCV, maraviroc, TAK-779, and HGS004 were determined. Results: Three patterns of susceptibilities were observed as follows: sigmoid inhibition curves with 50% inhibitory concentration similar to pretreatment virus [07J-week 0 (W0)], single mutants with decreased 50% inhibitory concentrations compared with 07J-W0, and mutants that contained ≥5 of 7 VCV resistance mutations with flattened inhibition curves and decreased or negative percent maximal inhibition. Substitutions such as S306P, which sensitized virus to CCR5 antagonists when present as single mutations, were not detected in the baseline virus population but were necessary for maximal resistance when incorporated into V3 backbones that included preexisting VCV resistance mutations. Conclusions: CCR5 antagonist resistance was reproduced only when a majority of V3 mutations were present. Minority V3 loop variants may serve as a scaffold upon which additional mutations lead to complete VCV resistance.
- Subjects :
- Receptors, CCR5
Anti-HIV Agents
Molecular Sequence Data
Population
HIV Infections
Microbial Sensitivity Tests
Drug resistance
CCR5 receptor antagonist
HIV Envelope Protein gp120
Biology
V3 loop
medicine.disease_cause
Article
Piperazines
Virus
Evolution, Molecular
Maraviroc
chemistry.chemical_compound
Cyclohexanes
Drug Resistance, Viral
medicine
Humans
Pharmacology (medical)
Amino Acid Sequence
education
education.field_of_study
Mutation
Triazoles
Amides
Virology
Peptide Fragments
Quaternary Ammonium Compounds
Pyrimidines
Infectious Diseases
chemistry
CCR5 Receptor Antagonists
HIV-1
Vicriviroc
medicine.drug
Subjects
Details
- ISSN :
- 15254135
- Volume :
- 55
- Database :
- OpenAIRE
- Journal :
- JAIDS Journal of Acquired Immune Deficiency Syndromes
- Accession number :
- edsair.doi.dedup.....8811d96d2a0eb63448b3ab8c98615a68