Lactobacilli: Blocking HIV/HSV by Mannose Binding

乳酸杆菌：通过甘露糖结合阻断 HIV/HSV

• 批准号: 7087939
• 负责人: LIN TAO
• 金额: $ 48.56万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087939
• 关键词: Alphaherpesvirinae; Lactobacillus; antiinfective agents; bacterial genetics; bacterial proteins; binding proteins; biotechnology; biotherapeutic agent; carbohydrate metabolism; clinical research; cooperative study; drug design /synthesis /production; female; human immunodeficiency virus; laboratory mouse; laboratory rabbit; laboratory rat; lectin; mannose; microorganism interaction; sexually transmitted diseases; tissue /cell culture; topical drug application; virus envelope

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.

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）引起了显着的发病率和死亡率。尽管这两种病毒都可以在性传播中，但生殖器疱疹的人更容易出现艾滋病毒。避孕套提供了出色的保护，但由于依从性差而受到限制。需要替代预防症，例如微生物剂，可供女性使用。 HIV是一种RNA病毒，而HSV是一种DNA病毒，但它们都具有高甘露糖的信封。巧合的是，某些乳杆菌自然地通过特定的结合蛋白依赖性糖摄取系统将甘露糖作为首选营养素。它的糖结合蛋白（凝集素）结合甘露糖。通过筛选近1,000种口服和阴道菌株的这种凝集素，我们选择了两种口腔中的菌株，从阴道乳酸杆菌中选择了五种菌株，可以捕获和代谢HIV/HSV的甲壳虫。因此，我们建议基于乳酸杆菌结合凝集素（LMBL）开发针对HIV和HSV的益生菌杀菌剂。我们假设LMBL+乳酸杆菌可以通过甘露糖特异性结合来阻止HIV和HSV感染。该项目是进行临床前研究。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）在体外对LMBL+乳杆菌对HSV-2和HIV-1的文档阻塞； （3）在小鼠疱疹模型中测试LMBL+乳杆菌在体内的抗HSV-2疗效； （4）评估兔和大鼠体内LMBL+乳杆菌的安全性； （5）优化益生菌菌心的配方，包装和保质期。这项研究完成后，我们将获得临床前数据并准备进行临床试验。这种方法的推定优势包括安全性，持续保护和成本效益。新方法优于所有其他微生物，可与合规性无关。它可以毫不显眼地保护女性。我们的长期目标是开发一种生物phi骨，可以作为疫苗或物理障碍的替代或补充，以保护妇女免受艾滋病毒和HSV的性传播。我们建议开发一种新颖的方法，以与自然敌人作斗争的艾滋病和疱疹病毒。我们已经隔离了一群友好的乳酸杆菌，可以捕获其糖病毒，从而杀死病毒，就像猫捕获小鼠一样。这种方法的成功发展可能会遏制全球艾滋病毒/HSV大流行，并最终挽救许多生命。