Lactobacilli as a Delivery Vehicle for Microbicides

描述（由申请人提供）：根据PAR-03-137，我们正在提交一份项目提案，设计和开发一系列有效的、高选择性的基于蛋白质的局部杀微生物剂。该应用的统一主题是使用非致病性粘膜细菌，乳酸菌，将这些蛋白质递送到阴道和直肠内的粘膜表面。经基因修饰的阴道乳酸菌分离株表达蛋白杀微生物剂，预计可防止HIV进入或进入宿主细胞和组织，从而减少感染。这三个高度整合的项目包括：1)设计和开发表达CD4变体的乳酸菌，这些变体能够与HIV进行多价高亲和相互作用，作为一种捕获和灭活粘膜内的HIV颗粒的手段；2)一个项目生产表达RANTES类似物的乳酸菌，作为趋化因子受体拮抗剂，阻断HIV进入宿主细胞和组织；3)一个项目以乳酸菌定向递送抗icam衍生物为中心，作为抑制细胞相关的HIV粘膜传播的新手段。这些项目都将得到中央核心设施的支持，包括行政、微生物和灵长类动物安全研究核心。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来实现其宿主的生产性感染。因此，这些方法不太可能被病毒蛋白质的高度易变性所绕过，这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.