Lactobacilli as a Delivery Vehicle for Microbicides

描述(由申请人提供)：为了响应PAR-03-137，我们提交了一份计划提案，以设计和开发一系列有效和高选择性的基于蛋白质的局部杀菌剂。该应用的统一主题是使用非致病的粘膜细菌乳杆菌，将这些蛋白质输送到阴道和直肠的粘膜表面。使用表达蛋白质杀微生物剂的转基因乳杆菌阴道分离株有望防止艾滋病毒进入或进入宿主细胞和组织，从而减少感染。这三个高度集成的项目包括：1)设计和开发能够与艾滋病毒进行多价高亲和力相互作用的乳杆菌表达CD4变体的方法，以此作为捕获和灭活粘膜内艾滋病毒颗粒的手段；2)生产表达RANTES类似物的乳杆菌计划，该类似物具有趋化因子受体拮抗剂的功能，并阻止艾滋病毒进入宿主细胞和组织；以及3)以乳酸菌为中心的项目导向输送抗ICAM衍生物，作为一种抑制艾滋病毒细胞相关粘膜传播的新方法。这些项目都将得到中央核心设施的支持，包括行政、微生物学和灵长类安全研究中心。重要的是，本申请中强调的三个独特项目已经完成了关键的“概念验证”研究，为本申请中概述的高级研究和开发活动奠定了基础。此外，这三种方法都针对HIV使用的保守功能机制，以实现对宿主的有效感染。因此，这些方法不太可能被病毒蛋白的高度变异性所绕过，而病毒蛋白是艾滋病毒的一个重要特性，它损害了有效预防性疫苗的开发。

DESCRIPTION (provided by applicant): In response to PAR-03-137, we are submitting a program proposal to design and develop a series of potent and highly selective protein-based topical microbicides. The unifying theme of the application is the use of non-pathogenic mucosal bacteria, lactobacilli, to deliver these proteins to mucosal surfaces within the vagina and rectum. The administration of genetically modified vaginal isolates of lactobacilli, expressing protein microbicides, is anticipated to prevent access or entry of HIV into host cells and tissues, thereby reducing infection. The three highly integrated projects include 1) an approach to design and develop lactobacilli expressing CD4 variants capable of a multivalent high-avidity interaction with HIV, as a means of trapping and inactivating HIV particles within the mucosa, 2) a program to produce lactobacilli expressing RANTES analogs that function as chemokine receptor antagonists and block HIV entry into cells and tissues of the host and 3) a project centered on lactobacillus-directed delivery of anti-ICAM derivatives as a novel means of inhibiting cell-associated mucosal transmission of HIV. These projects all will be supported by central core facilities, including administrative, microbiology, and primate safety study cores. Importantly, the three unique projects highlighted in this application have already completed key "proof-of-concept" studies that set the stage for the advanced research and development activities outlined in this application. Furthermore, all three approaches target conserved functional mechanisms used by HIV to achieve a productive infection of its host. As such, these approaches are less likely to be circumvented by the high mutability of viral proteins, an important property of HIV that has impaired the development of effective preventative vaccines.