title: Resistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41.
abstract: Here, we describe the genetic pathways taken by a human immunodeficiency virus type 1 (HIV-1) isolate, D101.12, to become resistant to the small molecule CCR5 inhibitor, vicriviroc (VCV), in vitro. Resistant D101.12 variants contained at least one substitution in the gp120 V3 region (H308P), plus one of two patterns of gp41 sequence changes involving the fusion peptide (FP) and a downstream residue: G514V+V535M or M518V+F519L+V535M. Studies of Env-chimeric and point-substituted viruses in peripheral blood mononuclear cells (PBMC) and TZM-bl cells showed that resistance can arise from the cooperative action of gp120 and gp41 changes, while retaining CCR5 usage. Modeling the VCV inhibition data from the two cell types suggests that D101.12 discriminates between high- and low-VCV affinity forms of CCR5 less than D1/85.16, a resistant virus with three FP substitutions.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA. canastassopoulou@partners.org
authors.forename: Cleo G
authors.initials: CG
authors.lastname: Anastassopoulou
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Depetris
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Thomas
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000187:drug effects; D065100:CCR5 Receptor Antagonists; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016415:Sequence Alignment
chemical_list: D065100:CCR5 Receptor Antagonists; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010879:Piperazines; D011743:Pyrimidines; C486781:vicriviroc