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Antimicrobial Agents and Chemotherapy, May 2008, p. 1751-1758, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.00707-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibitory Effect of PRO 2000, a Candidate Microbicide, on Dendritic Cell-Mediated Human Immunodeficiency Virus Transfer{triangledown}

Natalia Teleshova,1 Theresa Chang,1 Albert Profy,2 and Mary E. Klotman1*

Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York,1 Indevus Pharmaceuticals, Inc., Lexington, Massachusetts2

Received 30 May 2007/ Returned for modification 25 July 2007/ Accepted 27 February 2008

Without an effective vaccine against human immunodeficiency virus (HIV) infection, topical microbicide development has become a priority. The sulfonated polyanion PRO 2000, a candidate topical microbicide now in phase II/III clinical trials, blocks HIV infection of cervical tissue in vitro. Dendritic cells (DC) are among the first cell types to contact HIV in the genital tract and facilitate the spread of the virus. Thus, interfering with virus-DC interactions is a desirable characteristic of topical microbicides as long as that does not interfere with the normal function of DC. PRO 2000 present during capture of the replication-defective HIVJRFL reporter virus or replication-competent HIVBaL by monocyte-derived DC (MDDC) inhibited subsequent HIV transfer to target cells. Continuous exposure to PRO 2000 during MDDC-target cell coculture effectively inhibited HIV infection of target cells. PRO 2000 inhibited HIV capture by MDDC. In addition, the compound blocked R5 and X4 HIV envelope-mediated cell-cell fusion. Interestingly, simultaneous exposure to PRO 2000 and lipopolysaccharide attenuated the cytokine production in response to stimulation, suggesting that the compound altered DC function. While efficient blocking of MDDC-mediated virus transfer and infection in the highly permissive MDDC-T-cell environment reinforces the potential value of PRO 2000 as a topical microbicide against HIV, the impact of PRO 2000 on immune cell functions warrants careful evaluation.

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

{triangledown} Published ahead of print on 10 March 2008.

Antimicrobial Agents and Chemotherapy, May 2008, p. 1751-1758, Vol. 52, No. 5
0066-4804/08/$08.00+0     doi:10.1128/AAC.00707-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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