Preclinical evaluation of synthetic -2 RANTES as a candidate vaginal microbicide to target CCR5.
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.
Division of Basic Sciences, Institute of Human Virology, University of Maryland Biotechnology Institute, 725 West Lombard Street, S622, Baltimore, MD 21201, USA.
Tina M
TM
Kish-Catalone
Wuyuan
W
Lu
Robert C
RC
Gallo
Anthony L
AL
DeVico
D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology* / Q000633:toxicity; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5 / Q000494:pharmacology*; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011817:Rabbits; D014621:Vagina / Q000187:drug effects
D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D010446:Peptide Fragments; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1