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Antimicrobial Agents and Chemotherapy, December 2006, p. 4005-4010, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00588-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Biocompatibility of Solid-Dosage Forms of Anti-Human Immunodeficiency Virus Type 1 Microbicides with the Human Cervicovaginal Mucosa Modeled Ex Vivo{triangledown}

Radiana T. Trifonova, Jenna-Malia Pasicznyk, and Raina N. Fichorova*

Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Received 12 May 2006/ Returned for modification 13 July 2006/ Accepted 25 September 2006

Topical anti-human immunodeficiency virus (HIV) microbicides are being sought to reduce the spread of HIV type 1 (HIV-1) during sexual intercourse. The success of this strategy depends upon the selection of formulations compatible with the natural vaginal mucosal barrier. This study applied ex vivo-modeled human cervicovaginal epithelium to evaluate experimental solid-dosage forms of the anti-HIV-1 microbicide cellulose acetate 1,2-benzenedicarboxylate (CAP) and over-the-counter (OTC) vaginal products for their impact on inflammatory mediators regarded as potential HIV-1-enhancing risk factors. We assessed product-induced imbalances between interleukin-1{alpha} (IL-1{alpha}) and IL-1ß and the natural IL-1 receptor antagonist (IL-1RA) and changes in levels of IL-6, tumor necrosis factor alpha, IL-8, gamma interferon inducible protein 10 (IP-10), and macrophage inflammatory protein 3{alpha} (MIP-3{alpha}), known to recruit and activate monocytes, dendritic cells, and T cells to the inflamed mucosa. CAP film and gel formulation, similarly to the hydroxyethylcellulose universal vaginal placebo gel and the OTC K-Y moisturizing gel, were nontoxic and caused no significant changes in any inflammatory biomarker. In contrast, OTC vaginal cleansing and contraceptive films containing octoxynol-9 or nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles. IL-1{alpha}, IL-1ß, IL-8, and IP-10 were increased after treatment with both OTC vaginal cleansing and contraceptive films; however, MIP-3{alpha} was significantly elevated by the N-9-based film only (P < 0.01). Although both films increased extracellular IL-1RA, the cleansing film only significantly elevated the IL-1RA/IL-1 ratio (P < 0.001). The N-9-based film decreased intracellular IL-1RA (P < 0.05), which has anti-inflammatory intracrine functions. This study identifies immunoinflammatory biomarkers that can discriminate between formulations better than toxicity assays and should be clinically validated in relevance to the risk of HIV-1 acquisition.

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

{triangledown} Published ahead of print on 9 October 2006.

Antimicrobial Agents and Chemotherapy, December 2006, p. 4005-4010, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00588-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Trifonova, R. T., Doncel, G. F., Fichorova, R. N. (2009). Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses. Antimicrob. Agents Chemother. 53: 1490-1500 [Abstract] [Full Text]  
  • Jain, R. K., Jain, A., Maikhuri, J. P., Sharma, V. L., Dwivedi, A. K., Kiran Kumar, S.T.V.S., Mitra, K., Bajpai, V. K., Gupta, G. (2009). In vitro testing of rationally designed spermicides for selectively targeting human sperm in vagina to ensure safe contraception. Hum Reprod 24: 590-601 [Abstract] [Full Text]  


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