Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Anti-HIV Agents / pharmacology
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Antibodies, Monoclonal / chemistry
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CCR5 Receptor Antagonists
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DNA Primers / chemistry
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Drug Resistance, Viral*
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HIV Infections / drug therapy*
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HIV Infections / pathology
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HIV-1 / metabolism*
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Humans
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Molecular Sequence Data
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Piperazines / pharmacology*
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Pyrimidines / pharmacology*
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Receptors, CCR5 / metabolism
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Recombination, Genetic
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Sequence Homology, Amino Acid
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Time Factors
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Viral Envelope Proteins / chemistry
Substances
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Anti-HIV Agents
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Antibodies, Monoclonal
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CCR5 Receptor Antagonists
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DNA Primers
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Piperazines
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Pyrimidines
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Receptors, CCR5
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Viral Envelope Proteins
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vicriviroc
Associated data
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GENBANK/EU664612
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GENBANK/EU664613
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GENBANK/EU664614
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GENBANK/EU664615
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GENBANK/EU664616
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