Blocking Milk-Borne HIV by Commensal Bacteria

描述（由申请方提供）：本申请是对NIH RFA（DE-03-002）的回应，标题为“抑制HIV和寄生虫感染中的口腔粘液瘤先天免疫因子”。“具体来说，我们将研究一种新的口服先天免疫因子-甘露糖结合凝集素（MBL）-的细菌。 基本原理是人MBL结合并中和HIV，但它仅存在于血清中，而不存在于大多数HIV感染发生的粘膜表面。我们认为，粘膜表面上宿主MBL的缺乏可以至少部分地通过肠道细菌的MBL样凝集素来补偿。我们的初步研究表明，口腔中的一些乳酸杆菌产生中等水平的MBL样凝集素。像人MBL一样，微生物MBL样凝集素也结合HIV，因为HIV受体gpl 20富含甘露糖残基。乳杆菌自然生长在牛奶中（lacto=牛奶），是母乳喂养婴儿口腔和肠粘膜的最早定居者，是婴儿对感染性疾病（如腹泻）的先天免疫的起始组分。然而，微生物MBL样凝集素的亲和力不足以阻断HIV感染。我们假设，口腔乳酸杆菌，产生丰富的MBL样凝集素，对艾滋病毒具有高亲和力，可以从自发发生和/或诱导突变体分离。我们将通过追求两个具体目标来获得这些超级MBL乳酸杆菌： 第一章 通过筛选自发发生的和/或诱导的突变体获得超级MBL乳杆菌菌株。 （二） 超级MBL乳酸杆菌体外阻断HIV病毒的能力 在完成这项研究后，我们将获得一批超级MBL口服乳酸杆菌，这些乳酸杆菌可以高效地结合和中和HIV。这些细菌将用于进一步研究其结合特性、安全性、体内疗效和动物中的定殖，并最终用于人类志愿者。该项目的长期目标是选择自然捕获和杀死HIV病毒的食品级肠道细菌，并开发生物预防疗法，以安全地阻断HIV通过母乳喂养的垂直传播。

DESCRIPTION (provided by applicant): This application is in response to the NIH RFA (DE-03-002) entitled "Oral Mucosal Innate Immune Factors in the Inhibition of HIV and Opportunistic Infections." Specifically, we will study a novel factor of the oral innate immunity--mannose-binding lectin (MBL)--of commensal bacteria. The rationale is that the human MBL binds and neutralizes HIV, but it exists only in serum, not on mucosal surfaces where most HIV infections occur. We think that the lack of host MBL on mucosal surfaces can be compensated, at least in part, by MBL-like lectins of commensal bacteria. Our preliminary studies showed that some lactobacilli that colonize the oral cavity produce moderate levels of MBL-like lectin. Like the human MBL, microbial MBL-like lectins also bind HIV because the HIV receptor, gpl20, is rich in mannose-residues. Lactobacilli, which naturally grow in milk (lacto=milk), are earliest colonizers of the oral and intestinal mucosa in milk-fed infants and are a beginning component of the infant's innate immunity against infectious diseases, such as diarrhea. However, the affinity of microbial MBL-Iike lectins are not high enough to block HIV infections. We hypothesize that oral lactobacilli that produce abundant MBL-like lectins with a high affinity against HIV can be isolated from spontaneously occurred and/or induced mutants. We will obtain these super-MBL lactobacilli by pursuing two specific aims: 1) Obtain super-MBL Lactobacillus strains by screening spontaneously occurred and/or induced mutants. 2) Test the ability of super-MBL lactobacilli to block HIV viruses in vitro Upon completion of this study, we will have obtained a collection of super-MBL oral lactobacilli that bind and neutralize HIV with high efficiency. These bacteria will be used for further studies on their binding characteristics, safety, in vivo efficacy and colonization in animals and ultimately in human volunteers. The long-term goal of this project is to select food-grade commensal bacteria that naturally trap and kill HIV viruses and to develop a bioprophylactic therapy to safely block the vertical transmission of HIV via breastfeeding.