Preclinical evaluation of synthetic -2 RANTES as a candidate vaginal microbicide to target CCR5.

Abstract

A potential strategy that can be used to combat the worldwide AIDS epidemic is the development of a vaginal microbicide that prevents the sexual transmission of human immunodeficiency virus type 1 (HIV-1). Certain CC chemokines, including RANTES, MIP-1alpha, and MIP-1beta, might facilitate the development of such microbicides since they potently suppress HIV-1 infection by binding to CCR5, the viral coreceptor used by most sexually transmitted strains of HIV-1 to enter host cells. In this study, we evaluated whether a CCR5-specific fragment of RANTES that lacks two N-terminal residues (-2 RANTES) and possesses especially potent HIV-1 suppressive activity has toxicity profiles conducive to the advancement of testing in candidate microbicide formulations. Analyses were carried out with a synthetic version of the chemokine, which was formulated with either Novasomes 7474, a nonphospholipid liposome, or methylcellulose gel. Dialysis studies demonstrated that the formulated -2 RANTES was released from both vehicles and retained anti-HIV-1 activity. Preclinical toxicity studies carried out with Swiss Webster mouse and New Zealand White rabbit vaginal irritation models demonstrated minimal inflammation and minimal adverse changes in cervicovaginal tissue integrity after short-term (10 min) and long-term (24 h) exposure to formulations containing up to 1 mg/ml of -2 RANTES. Similarly, no toxicity was observed with formulations of bioactive murine RANTES in the Swiss Webster mouse vaginal irritation model. Overall, these preclinical studies suggest that -2 RANTES is suitable for further testing as a candidate anti-HIV-1 microbicide.

• Authors: Tina M Kish-Catalone, Wuyuan Lu, Robert C Gallo, Anthony L DeVico
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 50 Issue 4 Pg. 1497-509 (Apr 2006) ISSN: 0066-4804 [Print] United States
• PMID: 16569870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-HIV Agents
• Anti-Infective Agents, Local
• CCR5 Receptor Antagonists
• Chemokine CCL5
• Peptide Fragments
• Leukocyte Common Antigens
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Administration, Intravaginal
• Animals
• Anti-HIV Agents (pharmacology)
• Anti-Infective Agents, Local (pharmacology, toxicity)
• CCR5 Receptor Antagonists
• Chemokine CCL5 (pharmacology)
• Female
• HIV-1 (drug effects)
• Humans
• Leukocyte Common Antigens (analysis)
• Mice
• Peptide Fragments (pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Rabbits
• Vagina (drug effects)