Lactic acid bacteria in mucosal defense against HIV-1

描述（由申请人提供）：全世界每天有1,500多名儿童感染人类免疫缺陷病毒1型（HIV-1），大多数在发展中国家，近40%的婴儿感染是由于长期母乳喂养造成的。 在摄入感染HIV的母乳后，肠道粘膜表面是最有可能发生病毒传播的部位。影响新生儿肠道粘膜的最深刻的变化之一是出生时获得不同的肠道细菌种群。其中，乳酸菌（LAB）是胃肠道微生物群的正常组成部分，它们有助于加强粘膜屏障并调节针对外来抗原和肠道病原体的免疫反应性。尽管有相当多的证据表明LAB在增强粘膜防御方面发挥重要作用，但尚不清楚它们是否能抑制通过母乳喂养获得的产后HIV-1感染。在这项提案中，我们将评估的假设，LAB直接有助于肠道粘膜防御HIV-1通过分泌新的病毒抑制因子，干扰CCR 5。HIV-1是选择性地转移到肠上皮细胞的运输机制，涉及CCR 5，我们假设，LAB可能会干扰这一进程。迄今为止，尚未在新生儿中进行研究以鉴定具有抗HIV活性的LAB肠道菌株，并且几乎没有关于LAB抑制粘膜表面HIV感染的机制的数据。该提案的具体目的有两个方面：1）鉴定新生儿粪便样本中具有抗HIV活性的LAB，以支持其在麝香防御中的潜在作用，以及2）使用多种原代HIV-1分离株和肠上皮细胞转运模型在体外研究HIV-1抑制活性的机制，以确定抑制是否涉及CCR 5。这些研究的长期目标是确定具有抗HIV活性的LAB，可在发展中国家用作增强哺乳期母亲及其母乳喂养婴儿的天然粘膜防御屏障的手段。

DESCRIPTION (provided by applicant): Each day more than 1,500 children become infected with human immunodeficiency virus type 1 (HIV-1) worldwide, most in developing countries where nearly 40% of infant infections result from extended breastfeeding. Following ingestion of HIV-infected breastmilk, gut mucosal surfaces are the most likely site where virus transmission occurs. One of the most profound changes affecting the gut mucosa of newborns is the acquisition at birth of a diverse population of commensal bacteria. Among these, lactic acid bacteria (LAB) are a normal constituent of the microbiota of the gastrointestinal tract, where they help strengthen the mucosal barrier and modulate immune reactivity against foreign antigens and enteric pathogens. Despite considerable evidence that LAB play an important role in enhancing mucosal defenses, it is not known whether they can inhibit post-partum HIV-1 infection acquired through breast-feeding. In this proposal, we will evaluate the hypothesis that LAB contribute directly to the intestinal mucosal defense against HIV-1 through secretion of novel virus inhibitory factors that interfere with CCR5. HIV-1 is selectively transferred across intestinal epithelial cells by transport mechanisms involving CCR5 and we hypothesize that LAB may interfere with this process. To date, no studies have been conducted in neonates to identify intestinal strains of LAB with anti-HIV activity and few data exist on the mechanism(s) of LAB inhibition of HIV infection across mucosal surfaces. The specific aims of this proposal are two-fold: 1) to identify LAB with anti-HIV activity in neonatal stool samples in support of their potential role in muscoal defense, and 2) to investigate the mechanism of HIV-1 inhibitory actjvity in vitro using a diverse panel of primary HIV-1 isolates and intestinal epithelial cell transport models to determine whether inhibition involves CCR5. The long-term goal of these studies is to identify LAB with anti-HIV activity that can be utilized in developing countries as a means of augmenting the natural mucosal defense barrier in both lactating mothers and their breast-fed infants.