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

2008; American Society for Microbiology; Volume: 82; Issue: 16 Linguagem: Inglês

10.1128/jvi.00444-08

1098-5514

Athe Tsibris, Manish Sagar, Roy M. Gulick, Zhaohui Su, Michael D. Hughes, Wayne Greaves, Mani Subramanian, Charles Flexner, Françoise Giguel, Kay E. Leopold, Eoin Coakley, Daniel R. Kuritzkes,

Immune Cell Function and Interaction

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.