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Antimicrobial Agents and Chemotherapy, June 2004, p. 2025-2036, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2025-2036.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Candidate Topical Microbicides Bind Herpes Simplex Virus Glycoprotein B and Prevent Viral Entry and Cell-to-Cell Spread

Departments of Pediatrics,¹ Medicine, Mount Sinai School of Medicine, New York, New York,² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California,³ Department of Obstetrics and Gynecology, Rush University Medical Center,⁴ Department of Pharmacology, University of Illinois, Chicago, Illinois,⁵ Indevus Pharmaceuticals Inc., Lexington, Massachusetts⁶

Received 10 November 2003/ Returned for modification 8 January 2004/ Accepted 20 February 2004

Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.

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