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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{triangledown} ,{dagger}

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. Kuritzkes2,3*

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.

* 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

{triangledown} Published ahead of print on 21 May 2008.

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

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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