In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject.
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.
Tsibris
Athe M N
AM
Massachusetts General Hospital, Boston, Massachusetts, USA.
Sagar
Manish
M
Gulick
Roy M
RM
Su
Zhaohui
Z
Hughes
Michael
M
Greaves
Wayne
W
Subramanian
Mani
M
Flexner
Charles
C
Giguel
Françoise
F
Leopold
Kay E
KE
Coakley
Eoin
E
Kuritzkes
Daniel R
DR
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry; D065100:CCR5 Receptor Antagonists; D017931:DNA Primers / Q000737:chemistry; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000737:chemistry
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D017931:DNA Primers; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; C486781:vicriviroc