Lactobacilli as a Delivery Vehicle for Microbicides

描述（由申请人提供）：作为对PAR-03-137的回应，我们提交了一份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微生物剂的计划提案。该申请的统一主题是使用非致病性粘膜细菌乳酸杆菌将这些蛋白质递送到阴道和直肠内的粘膜表面。施用表达蛋白质杀微生物剂的乳杆菌的遗传修饰的阴道分离物，预期可防止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）设计和开发表达能够与HIV多价高亲合力相互作用的CD 4变体的乳酸杆菌的方法，作为在粘膜内捕获和灭活HIV颗粒的手段，2）产生表达RANTES类似物的乳杆菌的程序，所述RANTES类似物起趋化因子受体拮抗剂的作用并阻断HIV进入宿主的细胞和组织，和3）一个以乳酸杆菌为中心的抗ICAM衍生物的递送作为抑制HIV的细胞相关粘膜传播的新手段的项目。这些项目都将得到中央核心设施的支持，包括行政、微生物学和灵长类动物安全性研究核心。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，所有三种方法都针对HIV用于实现其宿主的生产性感染的保守功能机制。因此，这些方法不太可能被病毒蛋白的高度可变性所规避，这是HIV的一个重要特性，它阻碍了有效预防疫苗的开发。

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.