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Antimicrobial Agents and Chemotherapy, September 2005, p. 3607-3615, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3607-3615.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Candidate Sulfonated and Sulfated Topical Microbicides: Comparison of Anti-Human Immunodeficiency Virus Activities and Mechanisms of Action

Irini A. Scordi-Bello,1 Arevik Mosoian,1 Cejiang He,1 Yiban Chen,1 Yang Cheng,1 Gary A. Jarvis,5 Marla J. Keller,1 Kathleen Hogarty,1 Donald P. Waller,3 Albert T. Profy,4 Betsy C. Herold,2 and Mary E. Klotman1*

Departments of Medicine,1 Pediatrics, Mount Sinai School of Medicine, New York, New York,2 Department of Pharmacology, University of Illinois, Chicago, Illinois,3 Indevus Pharmaceuticals, Inc., Lexington, Massachusetts,4 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California5

Received 16 December 2004/ Returned for modification 8 March 2005/ Accepted 8 June 2005

Poly(styrene 4-sulfonate), cellulose sulfate, polymethylenehydroquinone, and PRO 2000 are sulfated or sulfonated polymers (SPs) under development as topical microbicides. They are presumed to work through similar mechanisms of action, although to date there has been no extensive comparison of their anti-human immunodeficiency virus activities. To determine whether any of these candidate microbicides offers a potential advantage, their in vitro activities, mechanisms of action, stabilities in biological secretions, and toxicities were compared. All four compounds were found to be active against X4, R5, and dualtropic primary isolates and against X4 and R5 laboratory-adapted strains in CD4+ T cells, macrophages, and single-coreceptor cell lines. Our single-cycle experiments using pseudotyped virus suggest that all four SPs function at the binding and entry stages of the viral life cycle but differ in degree of postentry effect. Surface plasmon resonance analyses demonstrate that SPs bind to X4 and R5 monomeric glycoprotein 120 with similar high binding affinities. When mixed with cervicovaginal lavage fluid, SPs maintain inhibitory activity at concentrations achievable in formulations.

* Corresponding author. Mailing address: Department of Medicine, Mount Sinai School of Medicine, Box 1090, New York, NY 10029. Phone: (212) 241-2950. Fax: (212) 534-3240. E-mail: mary.klotman{at}mssm.edu.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3607-3615, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3607-3615.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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