Cenicriviroc, a Novel CCR5 (R5) and CCR2 Antagonist, Shows In Vitro Activity against R5 Tropic HIV-2 Clinical Isolates

PLoS One. 2015 Aug 6;10(8):e0134904. doi: 10.1371/journal.pone.0134904. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / therapeutic use
  • CCR5 Receptor Antagonists / pharmacology*
  • CCR5 Receptor Antagonists / therapeutic use
  • Cells, Cultured
  • Coculture Techniques
  • Cyclohexanes / pharmacology
  • Cyclohexanes / therapeutic use
  • HIV Infections / drug therapy
  • HIV Infections / pathology*
  • HIV Infections / virology
  • HIV-2 / drug effects
  • HIV-2 / isolation & purification*
  • HIV-2 / physiology
  • Humans
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Maraviroc
  • Phenotype
  • Phytohemagglutinins / pharmacology
  • Receptors, CCR2 / antagonists & inhibitors*
  • Receptors, CCR2 / metabolism
  • Receptors, CCR5 / chemistry*
  • Receptors, CCR5 / metabolism
  • Sulfoxides
  • Triazoles / pharmacology
  • Triazoles / therapeutic use
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • CCR5 Receptor Antagonists
  • Cyclohexanes
  • Imidazoles
  • Phytohemagglutinins
  • Receptors, CCR2
  • Receptors, CCR5
  • Sulfoxides
  • Triazoles
  • cenicriviroc
  • Maraviroc

Grants and funding

Tobira Pharmaceutics graciously provided cenicriviroc. All the other experimental costs were supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). Tobira Pharmaceutics provided support in the form of salaries for author E.L., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.