title: Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir.
abstract: Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log(10) copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (Env) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.
authors.affiliation: Pfizer Global Research and Development, Sandwich, United Kingdom. mike.westby@pfizer.com
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Marilyn
authors.initials: M
authors.lastname: Lewis
authors.forename: Jeannette
authors.initials: J
authors.lastname: Whitcomb
authors.forename: Mike
authors.initials: M
authors.lastname: Youle
authors.forename: Anton L
authors.initials: AL
authors.lastname: Pozniak
authors.forename: Ian T
authors.initials: IT
authors.lastname: James
authors.forename: Tim M
authors.initials: TM
authors.lastname: Jenkins
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.forename: Elna
authors.initials: E
authors.lastname: van der Ryst
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D002999:Clone Cells; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D019143:Evolution, Molecular; D015752:Genes, env; D014644:Genetic Variation; D019302:HIV Envelope Protein gp160 / Q000235:genetics; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000077592:Maraviroc; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000097:blood; D019718:Receptors, CXCR4 / Q000097:blood*; D011995:Recombination, Genetic; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019302:HIV Envelope Protein gp160; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc