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Antimicrobial Agents and Chemotherapy, April 2006, p. 1497-1509, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1497-1509.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Preclinical Evaluation of Synthetic –2 RANTES as a Candidate Vaginal Microbicide To Target CCR5

Tina M. Kish-Catalone, Wuyuan Lu, Robert C. Gallo, and Anthony L. DeVico^*

Division of Basic Science, Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

Received 1 July 2005/ Returned for modification 1 September 2005/ Accepted 9 January 2006

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-1, and MIP-1ß, 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.

Present address: Department of Microbiology and Immunology and Centers for Sexually Transmitted Diseases and Molecular Therapeutics, Institute of Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129.

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