title: Cenicriviroc, a Novel CCR5 (R5) and CCR2 Antagonist, Shows In Vitro Activity against R5 Tropic HIV-2 Clinical Isolates.
abstract: BACKGROUND
  Maraviroc activity against HIV-2, a virus naturally resistant to different HIV-1 antiretroviral drugs, has been recently demonstrated. The aim of this study was to assess HIV-2 susceptibility to cenicriviroc, a novel, once-daily, dual CCR5 and CCR2 antagonist that has completed Phase 2b development in HIV-1 infection.
  
  
  METHODS
  Cenicriviroc phenotypic activity has been tested using a PBMC phenotypic susceptibility assay against four R5-, one X4- and one dual-tropic HIV-2 clinical primary isolates. All isolates were obtained by co-cultivation of PHA-activated PBMC from distinct HIV-2-infected CCR5-antagonist-naïve patients included in the French HIV-2 cohort and were previously tested for maraviroc susceptibility using the same protocol. HIV-2 tropism was determined by phenotypic assay using Ghost(3) cell lines.
  
  
  RESULTS
  Regarding the 4 R5 HIV-2 clinical isolates tested, effective concentration 50% EC50 for cenicriviroc were 0.03, 0.33, 0.45 and 0.98 nM, similar to those observed with maraviroc: 1.13, 0.58, 0.48 and 0.68 nM, respectively. Maximum percentages of inhibition (MPI) of cenicriviroc were 94, 94, 93 and 98%, similar to those observed with maraviroc (93, 90, 82, 100%, respectively). The dual- and X4-tropic HIV-2 strains were resistant to cenicriviroc with EC50 >1000 nM and MPI at 33% and 4%, respectively.
  
  
  CONCLUSIONS
  In this first study assessing HIV-2 susceptibility to cenicriviroc, we observed an in vitro activity against HIV-2 R5-tropic strains similar to that observed with maraviroc. Thus, cenicriviroc may offer a once-daily treatment opportunity in the limited therapeutic arsenal for HIV-2. Clinical studies are warranted.
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Visseaux
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Collin
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bertine
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Pharmacologie des antirétroviraux, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Peytavin
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Damond
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Service des Maladies Infectieuses et Tropicales, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Matheron
authors.affiliation: Tobira Therapeutics, Inc., South San Francisco, CA, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Lefebvre
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Brun-Vézinet
authors.affiliation: INSERM, IAME, UMR 1137, Paris, France; Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Virologie, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D018920:Coculture Techniques; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D015498:HIV-2 / Q000187:drug effects / Q000302:isolation & purification* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000077592:Maraviroc; D010641:Phenotype; D010835:Phytohemagglutinins / Q000494:pharmacology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000378:metabolism; D013454:Sulfoxides; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D007093:Imidazoles; D010835:Phytohemagglutinins; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D013454:Sulfoxides; D014230:Triazoles; C506967:cenicriviroc; D000077592:Maraviroc