title: Development of maraviroc, a CCR5 antagonist for treatment of HIV, using a novel tropism assay.
abstract: Assays to identify infectious organisms are critical for diagnosis and enabling the development of therapeutic agents. The demonstration that individuals with a 32-bp deletion within the CCR5 locus were resistant to human immunodeficiency virus (HIV) infection, while those heterozygous for the mutation progressed more slowly, led to the discovery of maraviroc (MVC), a CCR5 antagonist. As MVC is only active against CCR5-tropic strains of HIV, it was critical to develop a diagnostic assay to identify appropriate patients. Trofile™, a novel phenotypic tropism assay, was used to identify patients with CCR5-tropic virus for the MVC development program. Results of these clinical studies demonstrated that the assay correctly identified patients likely to respond to MVC. Over time, the performance characteristics of the phenotypic assay were enhanced, necessitating retesting of study samples. Genotypic tropism tests that have the potential to allow for local use and more rapid turnaround times are also being developed.
authors.affiliation: The Research Network, Sandwich, United Kingdom.
authors.forename: Elna
authors.initials: E
authors.lastname: van der Ryst
authors.affiliation: Pfizer Worldwide Research and Development, Groton, Connecticut.
authors.forename: Jayvant
authors.initials: J
authors.lastname: Heera
authors.affiliation: ViiV Healthcare, Research Triangle Park, North Carolina.
authors.forename: James
authors.initials: J
authors.lastname: Demarest
authors.affiliation: Pfizer Worldwide Research and Development, Pearl River, New York.
authors.forename: Charles
authors.initials: C
authors.lastname: Knirsch
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D001681:Biological Assay / Q000379:methods; D002986:Clinical Trials as Topic; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000187:drug effects / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D056189:Viral Tropism / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; C584933:CCR5 protein, human; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc
keywords: HIV; antiretroviral; assay; diagnostic; tropism