title: Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture.
abstract: 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.
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Center for Disease Control and Prevention, Atlanta, GA 30333, USA. cummins@sri.org
authors.forename: James E
authors.initials: JE
authors.lastname: Cummins
authors.forename: Jeannette
authors.initials: J
authors.lastname: Guarner
authors.forename: Lisa
authors.initials: L
authors.lastname: Flowers
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Guenthner
authors.forename: Jeanine
authors.initials: J
authors.lastname: Bartlett
authors.forename: Timothy
authors.initials: T
authors.lastname: Morken
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Grohskopf
authors.forename: Lynn
authors.initials: L
authors.lastname: Paxton
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology* / Q000633:toxicity; D002584:Cervix Uteri / Q000187:drug effects / Q000821:virology*; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010539:Permeability
chemical_list: D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local