Lactic acid bacteria in mucosal defense against HIV-1

描述(申请人提供)：全世界每天有1500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，那里近40%的婴儿感染是由延长母乳喂养造成的。在摄入感染艾滋病毒的母乳后，肠道粘膜表面最有可能发生病毒传播。影响新生儿肠道粘膜的最深刻的变化之一是在出生时获得了不同的共生菌群。其中，乳酸菌(LAB)是胃肠道微生物区系的正常组成部分，在那里它们有助于加强粘膜屏障，并调节对外来抗原和肠道病原体的免疫反应。尽管有相当多的证据表明LAB在增强粘膜防御方面发挥了重要作用，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。在这项提议中，我们将评估LAB通过分泌干扰CCR5的新的病毒抑制因子而直接促进肠道黏膜对HIV-1的防御的假设。HIV-1通过涉及CCR5的运输机制选择性地跨肠上皮细胞转移，我们假设LAB可能干预了这一过程。到目前为止，还没有研究在新生儿中鉴定LAB的肠道菌株具有抗艾滋病毒活性，关于LAB抑制艾滋病毒跨粘膜表面感染的机制(S)的数据也很少。这项建议的具体目的有两个：1)确定在新生儿粪便样本中具有抗HIV活性的Lab，以支持其在毒蛾防御中的潜在作用；2)使用一组不同的HIV-1原代分离株和肠道上皮细胞传输模型，在体外研究HIV-1抑制活性的机制，以确定抑制是否涉及CCR5。这些研究的长期目标是确定LAB具有抗HIV活性，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.