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Preclinical Testing of Candidate Topical Microbicides for Anti-Human Immunodeficiency Virus Type 1 Activity and Tissue Toxicity in a Human Cervical Explant Culture

James E. Cummins Jr.,^1* Jeannette Guarner,² Lisa Flowers,³ Patricia C. Guenthner,¹ Jeanine Bartlett,² Timothy Morken,^2, Lisa A. Grohskopf,⁴ Lynn Paxton,⁴ and Charlene S. Dezzutti^1,

Laboratory Branch,¹ Epidemiology Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention,⁴ Infectious Disease Pathology Activity, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,² Emory University School of Medicine, Atlanta, Georgia 30322³

Received 7 September 2006/ Returned for modification 7 November 2006/ Accepted 27 February 2007

A human cervical explant culture was utilized for the preclinical assessment of anti-human immunodeficiency virus type 1 (HIV-1) activity and tissue toxicity of formulated, candidate topical microbicides. Products tested included cellulose acetate 1,2-benzene dicarboxylate (CAP), a carrageenan-based product (PC-515), a naphthalene sulfonate polymer (PRO 2000), a lysine dendrimer (SPL7013), a nonnucleoside reverse transcriptase inhibitor (UC781), and an antimicrobial peptide (D2A21), along with their placebos. Cervical explants were cultured overnight with HIV-1 with or without product, washed, and monitored for signs of HIV-1 infection. HIV-1 infection was determined by p24gag levels in the basolateral medium and by immunohistochemical analysis of the explant. Product toxicity was measured by the MTT [1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan] assay and histology. CAP, PRO 2000, SPL7013, and UC781 consistently prevented HIV-1 infection in all explants tested. PC-515 and D2A21 prevented HIV-1 infection in 50% or fewer of the explants tested. Placebos did not prevent infection in any of the explants tested. With the exception of PRO 2000 (4%), the MTT assay and histological analysis of the other products and placebos showed minimal toxicity to the epithelium and submucosa. Collectively, these data suggest that this culture system can be used for evaluating the safety and efficacy of topical microbicides designed for vaginal use.

Published ahead of print on 12 March 2007.

Present address: Lab Vision-Neomarkers, 47790 Westinghouse Drive, Fremont, CA 94539.

Present address: University of Pittsburgh, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213.

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