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Antimicrobial Agents and Chemotherapy, January 2005, p. 323-335, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.323-335.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Anti-Human Immunodeficiency Virus Type 1 Microbicide Cellulose Acetate 1,2-Benzenedicarboxylate in a Human In Vitro Model of Vaginal Inflammation

R. N. Fichorova,1* F. Zhou,1 V. Ratnam,1 V. Atanassova,1 S. Jiang,2 N. Strick,3 and A. R. Neurath3

Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,1 Viral Immunology Laboratory,2 Biochemical Virology Laboratory, The Lindsley F. Kimball Research Institute of the New York Blood Center, New York, New York3

Received 18 May 2004/ Returned for modification 1 July 2004/ Accepted 9 September 2004

The sexual transmission of human immunodeficiency virus type 1 (HIV-1) is facilitated by inflammation and related epithelial barrier perturbation. Microbicides for vaginal applications are currently being developed to reduce the risk of HIV-1 transmission. However, little is known about their interference with epithelial immune function. In recent clinical trials, nonoxynol-9 (N-9), a virucide with a long history of intravaginal use as a contraceptive, failed to protect against HIV-1 possibly due to mucosal inflammatory damage. Cellulose acetate 1,2-benzenedicarboxylate, also named CAP (for "controls AIDS pandemic"), is an anti-HIV-1 microbicide selected from pharmaceutical excipients that are regarded as safe for oral administration but have not been assessed for potential effects on inflammatory factors in the vaginal environment. Here we use a sensitive human cell culture system to evaluate proinflammatory profiles of soluble CAP in reference to N-9 and known epithelial activators such as tumor necrosis factor alpha (TNF-{alpha}) and bacterial lysates. Within 6 h of exposure, TNF-{alpha} and N-9 triggered NF-{kappa}B and AP-1/cFos activation and upregulated interleukins and an array of chemokines by vaginal and polarized cervical epithelial cells. The induced proinflammatory status continued after removal of stimuli and was confirmed by enhanced transepithelial neutrophil migration. While sustaining stability and anti-HIV-1 activity in the epithelial environment, CAP did not increase the production of proinflammatory mediators during or after exposure, nor did it modify the epithelial resistance to leukocyte traffic. CAP attenuated some TNF-{alpha}-induced responses but did not interfere with epithelial cytokine responsiveness to gonococcal determinants. The described system may be useful for predicting proinflammatory side effects of other microbicide candidates for vaginal application.

* Corresponding author. Mailing address: Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, 221 Longwood Ave. RF468, Boston, MA 02115. Phone: (617) 278-0625. Fax: (617) 713-3018. E-mail: rfichorova{at}rics.bwh.harvard.edu.

Antimicrobial Agents and Chemotherapy, January 2005, p. 323-335, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.323-335.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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