title: HIV-1 predisposed to acquiring resistance to maraviroc (MVC) and other CCR5 antagonists in vitro has an inherent, low-level ability to utilize MVC-bound CCR5 for entry.
abstract: BACKGROUND
  Maraviroc (MVC) and other CCR5 antagonists are HIV-1 entry inhibitors that bind to- and alter the conformation of CCR5, such that CCR5 is no longer recognized by the viral gp120 envelope (Env) glycoproteins. Resistance to CCR5 antagonists results from HIV-1 Env acquiring the ability to utilize the drug-bound conformation of CCR5. Selecting for HIV-1 resistance to CCR5-antagonists in vitro is relatively difficult. However, the CCR5-using CC1/85 strain appears to be uniquely predisposed to acquiring resistance to several CCR5 antagonists in vitro including MVC, vicriviroc and AD101.
  
  
  RESULTS
  Here, we show that Env derived from the parental CC1/85 strain is inherently capable of a low affinity interaction with MVC-bound CCR5. However, this phenotype was only revealed in 293-Affinofile cells and NP2-CD4/CCR5 cells that express very high levels of CCR5, and was masked in TZM-bl, JC53 and U87-CD4/CCR5 cells as well as PBMC, which express comparatively lower levels of CCR5 and which are more commonly used to detect resistance to CCR5 antagonists.
  
  
  CONCLUSIONS
  Env derived from the CC1/85 strain of HIV-1 is inherently capable of a low-affinity interaction with MVC-bound CCR5, which helps explain the relative ease in which CC1/85 can acquire resistance to CCR5 antagonists in vitro. The detection of similar phenotypes in patients may identify those who could be at higher risk of virological failure on MVC.
authors: Center for Virology, Burnet Institute, Melbourne, Victoria, Australia.
authors: Michael
authors: M
authors: Roche
authors: Martin R
authors: MR
authors: Jakobsen
authors: Anne
authors: A
authors: Ellett
authors: Hamid
authors: H
authors: Salimiseyedabad
authors: Becky
authors: B
authors: Jubb
authors: Mike
authors: M
authors: Westby
authors: Benhur
authors: B
authors: Lee
authors: Sharon R
authors: SR
authors: Lewin
authors: Melissa J
authors: MJ
authors: Churchill
authors: Paul R
authors: PR
authors: Gorry
mesh_terms: D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D000077592:Maraviroc; D011485:Protein Binding / Q000187:drug effects; D019713:Receptors, CCR5 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc