title: HIV-1 clinical isolates resistant to CCR5 antagonists exhibit delayed entry kinetics that are corrected in the presence of drug.
abstract: HIV CCR5 antagonists select for env gene mutations that enable virus entry via drug-bound coreceptor. To investigate the mechanisms responsible for viral adaptation to drug-bound coreceptor-mediated entry, we studied viral isolates from three participants who developed CCR5 antagonist resistance during treatment with vicriviroc (VCV), an investigational small-molecule CCR5 antagonist. VCV-sensitive and -resistant viruses were isolated from one HIV subtype C- and two subtype B-infected participants; VCV-resistant isolates had mutations in the V3 loop of gp120 and were cross-resistant to TAK-779, an investigational antagonist, and maraviroc (MVC). All three resistant isolates contained a 306P mutation but had variable mutations elsewhere in the V3 stem. We used a virus-cell β-lactamase (BlaM) fusion assay to determine the entry kinetics of recombinant viruses that incorporated full-length VCV-sensitive and -resistant envelopes. VCV-resistant isolates exhibited delayed entry rates in the absence of drug, relative to pretherapy VCV-sensitive isolates. The addition of drug corrected these delays. These findings were generalizable across target cell types with a range of CD4 and CCR5 surface densities and were observed when either population-derived or clonal envelopes were used to construct recombinant viruses. V3 loop mutations alone were sufficient to restore virus entry in the presence of drug, and the accumulation of V3 mutations during VCV therapy led to progressively higher rates of viral entry. We propose that the restoration of pre-CCR5 antagonist therapy HIV entry kinetics drives the selection of V3 loop mutations and may represent a common mechanism that underlies the emergence of CCR5 antagonist resistance.
authors.affiliation: Brigham and Women’s Hospital, Boston, Massachusetts, USA.
authors.forename: Opass
authors.initials: O
authors.lastname: Putcharoen
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Henrich
authors.forename: Zixin
authors.initials: Z
authors.lastname: Hu
authors.forename: Jakapat
authors.initials: J
authors.lastname: Vanichanan
authors.forename: Eoin
authors.initials: E
authors.lastname: Coakley
authors.forename: Wayne
authors.initials: W
authors.lastname: Greaves
authors.forename: Roy M
authors.initials: RM
authors.lastname: Gulick
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.forename: Athe M N
authors.initials: AM
authors.lastname: Tsibris
mesh_terms: D000577:Amides / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D065100:CCR5 Receptor Antagonists; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D015699:HIV Envelope Protein gp120; D010879:Piperazines; D011743:Pyrimidines; D000644:Quaternary Ammonium Compounds; C119369:TAK 779; C486781:vicriviroc
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