Abstract
BackgroundMicrobicides 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.MethodsSusceptibility 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.ResultsA 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 signs 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.ConclusionThis 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.
Highlights
Microbicides must protect against STD pathogens without causing unacceptable toxic effects
Microbicide candidates A cross-section of candidate microbicides was selected, some of which have been reported to protect against HSV2 in mouse vaginal transmission models: N9 [28], Sulfonated polystyrene (SPS) [26], chlorhexidine [26], and BufferGel [29]
The small inset shows that immediately after delivery N9 reduced susceptibility about 6-fold, but by 5 minutes the mice were no longer protected since the fraction of mice treated with N9 that became infected was larger than the fraction of the control mice treated with phosphate buffered saline (PBS)
Summary
Microbicides must protect against STD pathogens without causing unacceptable toxic effects. Paradoxically N9 fails to protect women against HIV and other STD pathogens, most likely because it causes toxic effects that increase susceptibility. At present, screening for toxic effects in vivo is most often performed in the primate, rabbit, and mouse vaginal irritation models [4,5,6,7,8,9]. These models employ histology, colposcopy, and the release of inflammatory cytokines to detect toxic effects [4,5,6,8,9,10,11,12]. Animal models can be devised to test directly whether a microbicide increases susceptibility
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