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: Benoit Visseaux, Charlotte Charpentier, Gilles Collin, Mélanie Bertine, Gilles Peytavin, Florence Damond, Sophie Matheron, Eric Lefebvre, Françoise Brun-Vézinet, Diane Descamps, ANRS CO5 HIV-2 Cohort
• Journal: PloS one (PLoS One) Vol. 10 Issue 8 Pg. e0134904 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26247470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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