Susceptibility to genital herpes as a biomarker predictive of increased HIV risk: Expansion of a murine model of microbicide safety

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.
Antiviral therapy (Impact Factor: 3.02). 01/2009; 14(8):1113-24. DOI: 10.3851/IMP1463
Source: PubMed


A crucial gap in the development of microbicides for HIV prevention is the absence of models predictive of safety. Previous studies have demonstrated an increased susceptibility to genital herpes in mice following repeated applications of nonoxynol-9 (N-9). This study was designed to explore the underlying mechanisms, focusing on the effects that N-9 has on genital tract epithelium and to apply this expanded model to evaluate the safety of microbicides that have been advanced to clinical trials.
Mice were treated intravaginally with formulated 3.5% N-9, 1% tenofovir, 0.5% or 2% PRO 2000, hydroxyethylcellulose (HEC) placebo or no treatment and the effect on herpes simplex virus 2 (HSV-2) susceptibility, epithelial cell architecture, junctional proteins and inflammation were assessed.
Mice treated with seven daily doses of N-9, but not tenofovir, PRO 2000 or HEC, were significantly more susceptible to challenge with low doses of HSV-2; confocal microscopy demonstrated increased numbers of viral particles deep within the genital tract. N-9 disrupted the epithelium with loss of tight and adherens junctional proteins. By contrast, the epithelium was relatively preserved following tenofovir, PRO 2000 and HEC exposure. Additionally, N-9, but not the other microbicides, triggered a significant inflammatory response relative to untreated mice.
These findings indicate that disruption of the epithelium contributes to increased HSV-2 susceptibility and might provide a biomarker predictive of increased risk for HIV acquisition. The results are consistent with the safety outcomes of the recently completed Phase IIb clinical trial with 0.5% PRO 2000 gel, and predict that tenofovir gel will not adversely affect the genital tract.

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    • "Role of HS in HSV-2 infection HSV-2, the serotype responsible for the majority of genital herpes infections, is one of the most prevalent STIs worldwide . It is the most common cause of genital ulcers (Schomogyi et al. 1998; Sacks et al. 2004; Keller et al. 2005) and a well-recognized co-factor in the acquisition of HIV (Corey et al. 2004; Keller et al. 2005; Wilson et al. 2009). HSV-2 interacts with cell surface HSPGs during virus attachment and viral spread (Table I "
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    ABSTRACT: Cell surface heparan sulfate (HS), a polysaccharide composed of alternating uronic acid and glucosamine residues, represents a common link that many sexually transmitted infections (STIs) require for infection. Variable modifications within the monomeric units of HS chains together with their unique structural conformations generate heterogeneity, which expands the ability of HS to bind a diverse array of host and microbial proteins. Recent advances made in the field of glycobiology have critically enhanced our understanding of HS and its interactions with microbes and their significance in important human diseases. The role of HS has been elaborated for several STIs to include those caused by herpes simplex virus, human immunodeficiency virus, human papillomavirus, and Chlamydia. In addition, gonorrhea, syphilis, and yeast infections are also dependent on the presence of HS on human target cells. Critical steps such as pathogen adhesion or binding to host cells followed by internalization to enhance intracellular survival and possible spread to other cells are mediated by HS. In addition, HS guided cell signaling plays a role in the development of angiogenesis and inflammation associated with many STIs. Past and ongoing investigations are providing new push for the development of HS-mimetics and analogs as novel prevention strategies against many different STIs. This review article summarizes the significance of HS in STIs and describes how emerging new products that target HS can be used to control the spread of STIs.
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    • "We hypothesize that increased susceptiblity to HSV-2 in the murine model, whch may reflect changes in mucosal integrity and immune environment, will predict increased susceptibility to HIV infection. We applied these models to evaluate N-9, PRO 2000 and tenofovir [11]–[13]. The active pharmaceutical ingredients (APIs) were studied in the dual chamber model and the formulated gels in the mouse. "
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    Full-text · Article · Nov 2011 · PLoS ONE
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    • "A major problem in evaluating potential microbicides is a lack of models to predict safety. Recent work has identified new biomarkers that are consistent with safety outcomes seen in clinical trials (Mesquita et al., 2009; Moench et al., 2010; Wilson et al., 2009). "
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