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: 7001990
• 负责人: LIN TAO
• 金额: $ 48.87万
• 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/7001990
• 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）导致显着的发病率和死亡率。虽然这两种病毒都可以通过性传播，但患有生殖器疱疹的人更容易感染艾滋病毒。避孕套提供了极好的保护，但由于依从性差，效果有限。供女性使用的替代预防措施，例如杀微生物剂，是可取的。 HIV是RNA病毒，HSV是DNA病毒，但它们都有高甘露糖的包膜。巧合的是，某些乳杆菌通过特定的结合蛋白依赖性糖摄取系统自然地捕获甘露糖作为首选营养物质。其糖结合蛋白（凝集素）结合甘露糖。通过对近1000个口腔和阴道菌株中的此类凝集素进行筛选，我们从口腔乳杆菌中筛选出2株，从阴道乳杆菌中筛选出5株能够捕获并代谢HIV/HSV包膜甘露糖的菌株。因此，我们建议开发一种基于乳杆菌甘露糖结合凝集素（LMBL）的益生菌杀微生物剂，同时对抗 HIV 和 HSV。我们假设 LMBL+ 乳酸杆菌可以通过甘露糖特异性结合来阻断 HIV 和 HSV 感染。该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) 记录了 LMBL+ 乳酸杆菌在体外对 HSV-2 和 HIV-1 的阻断作用； (3)在小鼠疱疹模型中测试LMBL+乳酸杆菌的体内抗HSV-2功效； (4)评估LMBL+乳酸杆菌在兔和大鼠体内的安全性； (5)优化益生菌杀微生物剂的配方、包装和保质期。这项研究完成后，我们将获得临床前数据并为临床试验做好准备。这种方法的公认优点包括安全性、持久保护和成本效益。优于所有其他杀菌剂，新方法可以不依赖于合规性。它可以不引人注意、不引人注意地保护女性。我们的长期目标是开发一种生物预防方法，可以作为疫苗或物理屏障的替代品或补充，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方法来对抗艾滋病和疱疹病毒及其天敌。我们分离出了一组友好的乳酸杆菌，它们可以捕获病毒以获​​取糖分，从而杀死病毒，就像猫捕捉老鼠一样。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，并最终挽救许多生命。