Host Defense Against HIV-related Pulmonary Infections

描述(由申请人提供)： 肺部感染是艾滋病毒感染的常见并发症，也是艾滋病患者的常见死因。导致艾滋病毒感染的肺部病原体包括细菌(肺炎)、真菌(卡氏肺孢子虫)和分枝杆菌(结核病)。这些感染中的许多都可以进行抗菌治疗，但发展中国家可能没有这种治疗方法，而且抗生素耐药性是一个日益严重的问题。解决艾滋病毒相关肺部感染问题的一个更直接的办法是纠正艾滋病毒感染造成的宿主防御缺陷。该项目的长期目标是确定新的方法，以加强宿主对艾滋病毒感染患者肺部感染的防御。在这项申请中，我们将指导和协调一批既定的宿主防御调查人员，进行针对HIV相关肺部感染的研究。该项目的主题是探索遗传方法，以加强免疫效应细胞进入肺组织的输送，以增强艾滋病毒相关肺部感染的清除。我们推测，遗传方法可以用来增加局部信号，将免疫效应细胞募集到受感染的肺组织中，或者增加可用于募集的循环效应细胞池。四个互动研究项目将涉及： 1.CXCR3配体在抵抗卡氏肺孢子虫宿主防御中作为淋巴细胞募集信号(Shellito博士) 2.肺部感染的非依赖于CD4的疫苗策略(Kolls博士) 3.加强肺结核疫苗接种战略(拉姆齐博士、梅森博士) 4.提高对细菌性肺炎的造血反应的策略(施瓦辛伯格、纳尔逊和巴格比博士) 研究项目将由3个核心组成部分支持：行政核心(Shellito博士)、免疫学核心(张博士)、载体核心(Reiser博士) 项目研究将在与艾滋病毒感染相关的肺部感染动物模型中开发和验证新的免疫增强方法。然后，产生的数据将为未来应用于艾滋病毒感染患者提供基础。

DESCRIPTION (provided by applicant): Pulmonary infections are frequent complications of HIV infection and a common cause of death in patients with AIDS. Pulmonary pathogens complicating HIV infection include bacteria (pneumonia), fungi (Pneumocystis carinii), and mycobacteria (tuberculosis). Antimicrobial therapy is possible for many of these infections, but such therapies may not be available in developing countries and antibiotic resistance is an increasing problem. A more direct solution to the problem of HIV-related pulmonary infections is to correct the defects in host defense caused by HIV infection. The long-term objective of this Project is to identify new methods to augment host defense against pulmonary infection in HIV-infected patients. In this application, we will direct and coordinate a group of established investigators in host defense to conduct research targeted to HIV-related pulmonary infections. The Project theme is to explore genetic approaches to enhance the delivery of immune effector cells into lung tissue in order to augment clearance of HIV-related pulmonary infections. We postulate that genetic approaches can be used to either increase local signals for recruitment of immune effector cells into infected lung tissue or to increase the pool of circulating effector cells available for recruitment. Four interactive research projects will address: 1. CXCR3 ligands as signals for lymphocyte recruitment in host defense against P. carinii (Dr. Shellito) 2. CD4-independent vaccine strategies for pulmonary infections (Dr. Kolls) 3. Prime/boost vaccination strategies for pulmonary tuberculosis (Drs. Ramsay, Mason) 4. Strategies to increase hematopoietic responses to bacterial pneumonia (Drs. Schwarzenberger, Nelson, and Bagby) The research projects will be supported by 3 core components: Administrative Core (Dr. Shellito), Immunology Core (Dr. Zhang), Vector Core (Dr. Reiser) Project research will develop and validate new methods of immune augmentation in animal models of pulmonary infection relevant to HIV infection. Data generated will then provide a foundation for future applications to HIV-infected patients.