Vaginal Microbicides: Detecting Toxicities in Vivo that Paradoxically Increase Pathogen Transmission

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dc.contributor.author Cone, Richard A en_US
dc.contributor.author Hoen, Timothy en_US
dc.contributor.author Wong, XiXi en_US
dc.contributor.author Abusuwwa, Raed en_US
dc.contributor.author Anderson, Deborah J en_US
dc.contributor.author Moench, Thomas R en_US
dc.date.accessioned 2011-12-29T23:34:42Z
dc.date.available 2011-12-29T23:34:42Z
dc.date.copyright 2006 en_US
dc.date.issued 2006-6-1 en_US
dc.identifier.citation Cone, Richard A, Timothy Hoen, XiXi Wong, Raed Abusuwwa, Deborah J Anderson, Thomas R Moench. "Vaginal microbicides: detecting toxicities in vivo that paradoxically increase pathogen transmission." BMC Infectious Diseases 6:90. (2006) en_US
dc.identifier.issn 1471-2334 en_US
dc.identifier.uri http://hdl.handle.net/2144/2653
dc.description.abstract BACKGROUND: Microbicides must protect against STD pathogens without causing unacceptable toxic effects. Microbicides based on nonoxynol-9 (N9) and other detergents disrupt sperm, HSV and HIV membranes, and these agents are effective contraceptives. But paradoxically N9 fails to protect women against HIV and other STD pathogens, most likely because it causes toxic effects that increase susceptibility. The mouse HSV-2 vaginal transmission model reported here: (a) Directly tests for toxic effects that increase susceptibility to HSV-2, (b) Determines in vivo whether a microbicide can protect against HSV-2 transmission without causing toxicities that increase susceptibility, and (c) Identifies those toxic effects that best correlate with the increased HSV susceptibility. METHODS: Susceptibility was evaluated in progestin-treated mice by delivering a low-dose viral inoculum (0.1 ID50) at various times after delivering the candidate microbicide to detect whether the candidate increased the fraction of mice infected. Ten agents were tested – five detergents: nonionic (N9), cationic (benzalkonium chloride, BZK), anionic (sodium dodecylsulfate, SDS), the pair of detergents in C31G (C14AO and C16B); one surface active agent (chlorhexidine); two non-detergents (BufferGel®, and sulfonated polystyrene, SPS); and HEC placebo gel (hydroxyethylcellulose). Toxic effects were evaluated by histology, uptake of a 'dead cell' dye, colposcopy, enumeration of vaginal macrophages, and measurement of inflammatory cytokines. RESULTS: A single dose of N9 protected against HSV-2 for a few minutes but then rapidly increased susceptibility, which reached maximum at 12 hours. When applied at the minimal concentration needed for brief partial protection, all five detergents caused a subsequent increase in susceptibility at 12 hours of ~20–30-fold. Surprisingly, colposcopy failed to detect visible sign of the N9 toxic effect that increased susceptibility at 12 hours. Toxic effects that occurred contemporaneously with increased susceptibility were rapid exfoliation and re-growth of epithelial cell layers, entry of macrophages into the vaginal lumen, and release of one or more inflammatory cytokines (Il-1β, KC, MIP 1α, RANTES). The non-detergent microbicides and HEC placebo caused no significant increase in susceptibility or toxic effects. CONCLUSION: This mouse HSV-2 model provides a sensitive method to detect microbicide-induced toxicities that increase susceptibility to infection. In this model, there was no concentration at which detergents provided protection without significantly increasing susceptibility. en_US
dc.description.sponsorship JHU Woodrow Wilson Fellowship; National Institutes of Health (Program Project A1 45967) en_US
dc.language.iso en en_US
dc.publisher BioMed Central en_US
dc.rights Copyright 2006 Cone et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution 2.0 License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. en_US
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_US
dc.title Vaginal Microbicides: Detecting Toxicities in Vivo that Paradoxically Increase Pathogen Transmission en_US
dc.type article en_US
dc.identifier.doi 10.1186/1471-2334-6-90 en_US
dc.identifier.pubmedid 16740164 en_US
dc.identifier.pmcid 1523343 en_US

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