Lactobacilli: Blocking HIV/HSV by Mannose Binding

描述（由申请人提供）：人类免疫缺陷病毒（HIV）和单纯疱疹病毒（HSV）导致显著的发病率和死亡率。虽然这两种病毒都可以通过性传播，但生殖器疱疹患者更容易感染艾滋病毒。Conventional提供了很好的保护，但由于依从性差，效果有限。妇女最好使用杀微生物剂等替代性预防措施。HIV是一种RNA病毒，而HSV是一种DNA病毒，但它们都有一个高甘露糖的包膜。巧合的是，某些乳酸杆菌通过特异性结合蛋白依赖性糖摄取系统天然捕获甘露糖作为优选的营养素。其糖结合蛋白（凝集素）结合甘露糖。通过对近1,000株口腔和阴道菌株筛选这种凝集素，我们从口腔和阴道乳杆菌中选出了两株，五株，它们可以捕获和代谢HIV/HSV的包膜甘露糖。因此，我们建议开发一种益生菌杀微生物剂对艾滋病毒和单纯疱疹病毒的基础上乳杆菌甘露糖结合凝集素（LMBL）。我们假设LMBL+乳酸杆菌可以通过甘露糖特异性结合阻断HIV和HSV感染。本项目旨在进行临床前研究。我们将追求五个具体目标：（1）候选LMBL+乳酸杆菌的表型和基因型分析;（2）记录LMBL+乳酸杆菌对HSV-2和HIV-1的体外阻断作用;（3）在小鼠疱疹模型中测试LMBL+乳酸杆菌的体内抗HSV-2效力;（4）在兔和大鼠中评估LMBL+乳酸杆菌的体内安全性;和（5）优化益生菌杀微生物剂的配方、包装和保质期。完成本研究后，我们将获得临床前数据，并为临床试验做好准备。这种方法的假定优点包括安全、持久保护和成本效益。优于所有其他杀微生物剂的上级新方法可以是不依赖于顺应性的。它可以保护妇女不引人注目和不显眼。我们的长期目标是开发一种生物预防方法，作为疫苗或物理屏障的替代或补充，以保护妇女免受艾滋病毒和单纯疱疹病毒的性传播。我们建议开发一种新的方法来对抗艾滋病和疱疹病毒与它们的天敌。我们已经分离出了一组友好的乳酸杆菌，它们可以捕获病毒，从而杀死病毒，就像猫抓老鼠一样。这种方法的成功开发可能会遏制全球HIV/HSV流行，并最终挽救许多生命。

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV) and herpes simplex virus (HSV) cause significant morbidity and mortality. While both viruses can be transmitted sexually, people with genital herpes are more prone to HIV. Condoms offer excellent protection, but the effect has been limited due to poor compliance. Alternative prophylaxis, such as microbicides, for use by women are desirable. HIV is an RNA virus, while HSV is a DNA virus, but they both have an envelope with high mannose. Coincidentally, certain lactobacilli naturally capture mannose as a preferred nutrient by a specific binding protein-dependent sugar uptake system. Its sugar-binding protein (lectin) binds mannose. By screening nearly 1,000 oral and vaginal strains for such lectin, we have selected two strains from oral and five from vaginal lactobacilli that can capture and metabolize envelope mannose of HIV/HSV. Therefore, we propose to develop a probiotic microbicide against both HIV and HSV based on Lactobacillus mannose-binding lectin (LMBL). We hypothesize that LMBL+ lactobacilli can block both HIV and HSV infections by mannose-specific binding. This project is to perform preclinical studies. We will pursue five specific aims: (1) phenotypic and genotypic analyses of candidate LMBL+ lactobacilli; (2) document blockage of LMBL+ lactobacilli against HSV-2 and HIV-1 in vitro; (3) test anti-HSV-2 efficacy of LMBL+ lactobacilli in vivo in a mouse herpes model; (4) assess safety of LMBL+ lactobacilli in vivo in rabbits and rats; and (5) optimize formulation, packaging, and shelf life of the probiotic microbicide. Upon completion of this study, we will achieve preclinical data and be ready for clinical trials. Putative advantages of this method include safety, persistent protection and cost-efficiency. Superior to all other, microbicides, the new method can be compliance-independent. It can protect women unobtrusively and inconspicuously. Our long-term goal is to develop a bio-prophylaxis that can serve as an alternative or supplement to vaccines or physical barriers to protect women against sexual transmission of HIV and HSV. We propose to develop a novel method to fight AIDS and herpes viruses with their natural enemies. We have isolated a group of friendly lactobacilli, which can capture viruses for their sugar, thereby killing the virus, much like cats catching mice. Successful development of this method will likely curb the global HIV/HSV pandemic and ultimately save many lives.