title: The dual CCR5 and CCR2 inhibitor cenicriviroc does not redistribute HIV into extracellular space: implications for plasma viral load and intracellular DNA decline.
abstract: OBJECTIVE
  Cenicriviroc is a potent antagonist of the chemokine coreceptors 5 and 2 (CCR5/CCR2) and blocks HIV-1 entry. The CCR5 inhibitor maraviroc has been shown in tissue culture to be able to repel cell-free virions from the cell surface into extracellular space. We hypothesized that cenicriviroc might exhibit a similar effect, and tested this using clinical samples from the Phase IIb study 652-2-202, by measuring rates of intracellular DNA decline. We also monitored viral RNA levels in culture fluids.
  
  
  METHODS
  We infected PM-1 cells with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of cenicriviroc (20 nM) or maraviroc (50 nM) or controls. Viral load levels and p24 were measured by ELISA, quantitative PCR and quantitative real-time reverse transcription PCR at 4 h post-infection. Frozen PBMC DNA samples from 30 patients with virological success in the Phase IIb study were studied, as were early and late reverse transcript levels. Docking studies compared binding between cenicriviroc/CCR5 and maraviroc/CCR5.
  
  
  RESULTS
  Unlike maraviroc, cenicriviroc did not cause an increase in the amount of virus present in culture fluids at 4 h compared with baseline. The use of cenicriviroc did, however, result in lower levels of intracellular viral DNA after 4 h. Structural modelling indicates that cenicriviroc binds more deeply than maraviroc to the hydrophobic pocket of CCR5, providing an explanation for the absence of viral rebound with cenicriviroc.
  
  
  CONCLUSIONS
  In contrast to maraviroc, cenicriviroc does not repel virus back into extracellular space. Differences in results may be due to superior binding of cenicriviroc to CCR5 compared with maraviroc.
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada Department of Experimental Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Kramer
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada Department of Experimental Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Said
authors.initials: S
authors.lastname: Hassounah
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Colby-Germinario
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: Tobira Therapeutics Inc., South San Francisco, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lefebvre
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.affiliation: McGill AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada Department of Experimental Medicine, McGill University, Montreal, QC, Canada Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada mark.wainberg@mcgill.ca.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D017322:Clinical Trials, Phase II as Topic; D003470:Culture Media; D004279:DNA, Viral / Q000032:analysis*; D004797:Enzyme-Linked Immunosorbent Assay; D005110:Extracellular Space / Q000821:virology; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D013454:Sulfoxides; D019562:Viral Load; D014776:Virus Cultivation
chemical_list: D019380:Anti-HIV Agents; D003470:Culture Media; D004279:DNA, Viral; D007093:Imidazoles; D013454:Sulfoxides; C506967:cenicriviroc
keywords: antiretrovirals; antiviral; entry inhibitors