Lactobacilli: Blocking HIV/HSV by Mannose Binding

描述(申请人提供)：人类免疫缺陷病毒(HIV)和单纯疱疹病毒(HSV)会导致严重的发病率和死亡率。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。避孕套提供了极好的保护，但由于遵从性差，效果有限。妇女使用的替代预防措施，如杀菌剂是可取的。HIV是一种RNA病毒，而HSV是一种DNA病毒，但它们都有一个含有高甘露糖的信封。巧合的是，某些乳杆菌通过一种特定的结合蛋白依赖的糖吸收系统，自然地将甘露糖作为首选营养物质。它的糖结合蛋白(凝集素)与甘露糖结合。通过对近1000株口腔和阴道菌株的筛选，我们从口腔和阴道乳杆菌中筛选出2株能够捕获和代谢HIV/HSV包膜甘露糖的菌株和5株来自阴道的乳酸杆菌。因此，我们建议开发一种基于乳杆菌甘露糖结合凝集素(LMBL)的同时抗HIV和HSV的益生菌杀菌剂。我们推测LMBL乳酸菌可以通过甘露糖特异性结合来阻断HIV和HSV感染。这个项目是为了进行临床前研究。我们将追求五个具体目标：(1)候选LMBL乳酸菌的表型和基因分型分析；(2)证明LMBL乳酸菌在体外对HSV-2和HIV-1的阻断作用；(3)在小鼠疱疹模型上测试LMBL乳酸菌的体内抗HSV-2效果；(4)评估LMBL乳酸菌在兔和大鼠体内的安全性；以及(5)优化益生菌杀菌剂的处方、包装和保质期。这项研究完成后，我们将获得临床前数据，并为临床试验做好准备。这种方法的公认优点包括安全、持久保护和成本效益。与所有其他杀微生物剂相比，这种新方法可以是不依从性的。它可以在不显眼的情况下保护女性。我们的长期目标是开发一种生物预防措施，作为疫苗或身体屏障的替代或补充，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的天敌。我们已经分离出一组友好的乳酸菌，它们可以捕捉病毒的糖分，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艾滋病毒/单纯疱疹病毒的流行，并最终拯救许多人的生命。

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.