title: Chemokine (C-C motif) receptor 5-using envelopes predominate in dual/mixed-tropic HIV from the plasma of drug-naive individuals.
abstract: OBJECTIVE
  HIV-1 utilizes CD4 and either chemokine (C-C motif) receptor 5 (CCR5) or chemokine (C-X-C motif) receptor 4 (CXCR4) to gain entry into host cells. Small molecule CCR5 antagonists are currently being developed for the treatment of HIV-1 infection. Because HIV-1 may also use CXCR4 for entry, the use of CCR5 entry inhibitors is controversial for patients harboring CCR5-using and CXCR4-using (dual/mixed-tropic) viruses. The goal of the present study was to determine the proportion of CCR5-tropic and CXCR4-tropic viruses in dual/mixed-tropic virus isolates from drug-naïve patients and the phenotypic and genotypic relationships of viruses that use CCR5 or CXCR4 or both.
  
  
  METHODS
  Fourteen antiretroviral-naive HIV-1-infected patients were identified as having population coreceptor tropism readout of dual/mixed-tropic viruses. Intrapatient comparisons of coreceptor tropism and genotype of env clones were conducted on plasma virus from each patient.
  
  
  METHODS
  Population HIV-1 envelope tropism and susceptibility to the CCR5 entry inhibitor, aplaviroc, were performed using the Monogram Biosciences Trofile Assay. Twelve env clones from each patient were analyzed for coreceptor tropism, aplaviroc sensitivity, genotype, and intrapatient phylogenetic relationships.
  
  
  RESULTS
  Viral populations from antiretroviral-naive patients with dual/mixed-tropic virus are composed primarily of CCR5-tropic env clones mixed with those that use both coreceptors (R5X4-tropic) and, occasionally, CXCR4-tropic env clones. Interestingly, the efficiency of CXCR4 use by R5X4-tropic env clones varied with their genetic relationships to CCR5-tropic env clones from the same patient.
  
  
  CONCLUSIONS
  These data show that the majority of viruses in these dual/mixed-tropic populations use CCR5 and suggest that antiretroviral-naive patients may benefit from combination therapy that includes CCR5 entry inhibitors.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. david.m.irlbeck@gsk.com
authors.forename: David M
authors.initials: DM
authors.lastname: Irlbeck
authors.forename: Heather
authors.initials: H
authors.lastname: Amrine-Madsen
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
authors.forename: Celia C
authors.initials: CC
authors.lastname: Labranche
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
mesh_terms: D001565:Benzoates / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D054659:Diketopiperazines; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D010802:Phylogeny; D010879:Piperazines / Q000494:pharmacology; D012367:RNA, Viral / Q000097:blood; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D018523:Tropism; D054299:env Gene Products, Human Immunodeficiency Virus
chemical_list: D001565:Benzoates; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D013141:Spiro Compounds; D054299:env Gene Products, Human Immunodeficiency Virus; C499671:aplaviroc