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Mapping and Characterization of Vicriviroc Resistance Mutations From HIV-1 Isolated from Treatment-Experienced Subjects Enrolled in a Phase II Study (VICTOR-E1)

McNicholas, Paul M PhD; Mann, Paul A MPH; BSc, Lisa Wojcik; PhD, Ping Qiu; Lee, Erin RN; McCarthy, Michael MD; Shen, Junwu PhD; Black, Todd A PhD; Strizki, Julie M PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2011 - Volume 56 - Issue 3 - p 222-229
doi: 10.1097/QAI.0b013e3181ff63ee
Basic and Translational Science

Objectives: In the phase 2 VICTOR-E1 study, treatment-experienced subjects receiving 20 mg or 30 mg of the CCR5 antagonist vicriviroc (VCV), with a boosted protease containing optimized background regimen, experienced significantly greater reductions in HIV-1 viral load compared with control subjects. Among the 79 VCV-treated subjects, 15 experienced virologic failure, and of these 5 had VCV-resistant virus. This study investigated the molecular basis for the changes in susceptibility to VCV in these subjects.

Methods: Sequence analysis and phenotypic susceptibility testing was performed on envelope clones from VCV-resistant virus. For select clones, an exchange of mutations in the V3 loop was performed between phenotypically resistant clones and the corresponding susceptible clones.

Results: Phenotypic resistance was manifest by reductions in the maximum percent inhibition. Clonal analysis of envelopes from the 5 subjects identified multiple amino acid changes in gp160 that were exclusive to the resistant clones, however, none of the changes were conserved between subjects. Introduction of V3 loop substitutions from the resistant clones into the matched susceptible clones was not sufficient to reproduce the resistant phenotype. Likewise, changing the substitutions in the V3 loops from resistant clones to match susceptible clones only restored susceptibility in 1 clone.

Conclusions: There were no clearly conserved patterns of mutations in gp160 associated with phenotypic resistance to VCV and mutations both within and outside of the V3 loop contributed to the resistance phenotype. These data suggest that genotypic tests for VCV susceptibility may require larger training sets and additional information beyond V3 sequences.

From the *Department of Infectious Diseases; †Department of Molecular Design and Informatics; ‡Department of Clinical Research; and §Department of Biostatistics Merck Research Labs, Kenilworth, NJ.

Received for publication August 10, 2010; accepted September 28, 2010.

Parts of this work were presented at the 2009 Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA.

All authors are employees of Merck Research Laboratories.

The authors have no funding or conflicts of interest to disclose.

Correspondence to: Paul M. McNicholas, PhD, Merck Research Laboratories, Department of Infectious Diseases, 2015 Galloping Hill Road, Kenilworth, NJ 07033 (e-mail: paul.mcnicholas@merck.com).

Copyright © 2011 Wolters Kluwer Health, Inc. All rights reserved.