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Journal of Virology, August 2008, p. 8210-8214, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00444-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vivo Emergence of Vicriviroc Resistance in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Subject ^,

Athe M. N. Tsibris,^1,2 Manish Sagar,^2,3 Roy M. Gulick,⁴ Zhaohui Su,⁵ Michael Hughes,⁵ Wayne Greaves,⁶ Mani Subramanian,⁷ Charles Flexner,⁸ Françoise Giguel,¹ Kay E. Leopold,⁹ Eoin Coakley,¹⁰ and Daniel R. Kuritzkes^2,3*

Massachusetts General Hospital, Boston, Massachusetts,¹ Harvard Medical School, Boston, Massachusetts,² Brigham and Women's Hospital, Boston, Massachusetts,³ Weill Medical College, Cornell University, New York, New York,⁴ Harvard School of Public Health, Boston, Massachusetts,⁵ Schering-Plough Research Institute, Kenilworth, New Jersey,⁶ Human Genome Sciences, Rockville, Maryland,⁷ Johns Hopkins University, Baltimore, Maryland,⁸ Harvard University, Cambridge, Massachusetts,⁹ Monogram Biosciences, South San Francisco, California,¹⁰

Received 28 February 2008/ Accepted 24 April 2008

Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.

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* Corresponding author. Mailing address: Section of Retroviral Therapeutics, Brigham and Women's Hospital, 65 Landsdowne St., Room 435, Cambridge, MA 02139. Phone: (617) 768-8371. Fax: (617) 768-8738. E-mail: dkuritzkes{at}partners.org

Published ahead of print on 21 May 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, August 2008, p. 8210-8214, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00444-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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