A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety

Galen, Benjamin T.; Martín, Andrea P.; Hazrati, Ehsan; Garin, Alexandre; Guzman, Esmeralda; Wilson, Sarah S.; Porter, David D.; Lira, Sérgio A.; Keller, Marla J.; Herold, Betsy C.

doi:10.1086/513279

Cited by 63 publications

(65 citation statements)

References 41 publications

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“…Numerous vaginal microbicides that have been tested in humans possess strong surfactant properties and, therefore, may also alter mucus pore size. However, most of these agents caused substantial toxicity to the vaginal epithelium by damaging cell membranes, and therefore failed to reduce (or in some cases even increased) infection rates (42)(43)(44)(45). Thus, whereas our results suggest that the use of surface-active agents may help limit infection by decreasing the flux of pathogens to the epithelium, this hypothesis can only be tested with agents that do not simultaneously compromise the epithelial cell layer.…”

Section: Discussionmentioning

confidence: 65%

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Lai

Wang²,

Hida³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

339

343

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The mechanisms by which mucus helps prevent viruses from infecting mucosal surfaces are not well understood. We engineered non-mucoadhesive nanoparticles of various sizes and used them as probes to determine the spacing between mucin fibers (pore sizes) in fresh undiluted human cervicovaginal mucus (CVM) obtained from volunteers with healthy vaginal microflora. We found that most pores in CVM have diameters significantly larger than human viruses (average pore size 340 ± 70 nm; range approximately 50–1800 nm). This mesh structure is substantially more open than the 15–100-nm spacing expected assuming mucus consists primarily of a random array of individual mucin fibers. Addition of a nonionic detergent to CVM caused the average pore size to decrease to 130 ± 50 nm. This suggests hydrophobic interactions between lipid-coated “naked” protein regions on mucins normally cause mucin fibers to self-condense and/or bundle with other fibers, creating mucin “cables” at least three times thicker than individual mucin fibers. Although the native mesh structure is not tight enough to trap most viruses, we found that herpes simplex virus (approximately 180 nm) was strongly trapped in CVM, moving at least 8,000-fold slower than non-mucoadhesive 200-nm nanoparticles. This work provides an accurate measurement of the pore structure of fresh, hydrated ex vivo CVM and demonstrates that mucoadhesion, rather than steric obstruction, may be a critical protective mechanism against a major sexually transmitted virus and perhaps other viruses.

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Section: Discussionmentioning

confidence: 65%

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Lai

Wang²,

Hida³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

339

343

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show abstract

“…While N9, BZK, and SDS were selected as positive controls in models of vaginal irritation and inflammation, as reported in previous works (2,9,13,15,16), carboxymethyl cellulose (CMC; which is widely used as a microbicide excipient and control) and TFV (a microbicide candidate which is proven to be efficacious and safe [1]) were chosen as negative controls. N9 and TFV were purchased from LKT Laboratories, Inc., and Molekula Limited (United Kingdom), respectively.…”

Section: Reagentsmentioning

confidence: 99%

“…Specifically, N9 did not prevent HIV-1 infection when used at a low frequency, and it even increased the risk of HIV-1 infection by frequent use (42). A series of studies that followed found that genital inflammation and the disruption of the cervicovaginal epithelium induced by microbicides are critical risk factors associated with the incidence of HIV-1 infection (9,13,15,16,18).…”

mentioning

confidence: 99%

“…In fact, a number of animal and human studies have produced evidence that the levels of proinflammatory cytokine interleukin 1 (IL-1), IL-6, and chemokines IL-8, monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 3␣ (MIP-3␣) in cervicovaginal lavage (CVL) fluid positively correlate with histopathological and clinical signs of vaginal inflammation (2,9,(13)(14)(15)(16). Accordingly, these cytokines/chemokines have been defined as biomarkers of cervicovaginal inflammation.…”

mentioning

confidence: 99%

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L-Selectin and P-Selectin Are Novel Biomarkers of Cervicovaginal Inflammation for Preclinical Mucosal Safety Assessment of Anti-HIV-1 Microbicide

Zhong

Yang

et al. 2012

Antimicrob Agents Chemother

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A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.

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“…Progesterone is frequently used in vaginal infection models to synchronize estrous cycles and to increase susceptibility by thinning out the vaginal layer, including models of simian immunodeficiency virus/SHIV infection in nonhuman primates (13,14,67,69,70,78) and mouse models of HIV-1 (68,79), human papillomavirus (HPV) (80), and herpes simplex virus 2 (HSV-2) (81) infection. Increased susceptibility to viral infection after mucosal N-9 application has been described in models of HPV infection (80) and both vaginal and rectal HSV-2 infection (72,82,83). In addition, an increased frequency of HIV-1 infection has been found in female sex workers after application of high doses of N-9 (84).…”

Section: Discussionmentioning

confidence: 99%

Antibody and Antiretroviral Preexposure Prophylaxis Prevent Cervicovaginal HIV-1 Infection in a Transgenic Mouse Model

Gruell

Bournazos

Ravetch

et al. 2013

J Virol

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The development of an effective vaccine preventing HIV-1 infection remains elusive. Thus, the development of novel approaches capable of preventing HIV-1 transmission is of paramount importance. However, this is partly hindered by the lack of an easily accessible small-animal model to rapidly measure viral entry. Here, we report the generation of a human CD4-and human CCR5-expressing transgenic luciferase reporter mouse that facilitates measurement of peritoneal and genitomucosal HIV-1 pseudovirus entry in vivo. We show that antibodies and antiretrovirals mediate preexposure protection in this mouse model and that the serum antibody concentration required for protection from cervicovaginal infection is comparable to that required to protect macaques. Our results suggest that this system represents a model for the preclinical evaluation of prophylactic or vaccine candidates. It further supports the idea that broadly neutralizing antibodies should be evaluated for use as preexposure prophylaxis in clinical trials.

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A Comprehensive Murine Model to Evaluate Topical Vaginal Microbicides: Mucosal Inflammation and Susceptibility to Genital Herpes as Surrogate Markers of Safety

Cited by 63 publications

References 41 publications

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

L-Selectin and P-Selectin Are Novel Biomarkers of Cervicovaginal Inflammation for Preclinical Mucosal Safety Assessment of Anti-HIV-1 Microbicide

Antibody and Antiretroviral Preexposure Prophylaxis Prevent Cervicovaginal HIV-1 Infection in a Transgenic Mouse Model

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