Oral Mucosal Immunity in Vulnerable HIV Infected Populations

易受艾滋病毒感染人群的口腔粘膜免疫

• 批准号: 7869420
• 负责人: AARON WEINBERG
• 金额: $ 166.56万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869420
• 关键词: Oral; Mucosal; Immunity; Vulnerable; HIV

DESCRIPTION (provided by applicant): Vulnerable populations at risk of acquiring HIV include racial minorities. While African Americans make up13% of the US population, they account for about half of the HIV/AIDS new diagnoses. Since 2000, several reports have suggested that oral HPV growths are increasing in people with HIV/AIDS on HAART, and that this is more prevalent in vulnerable populations, such as African Americans than Whites. The central hypothesis of this Program Project is that alterations in innate defense mechanisms determine susceptibility to oral complications following HIV infection. Human beta defensins (hBDs) have been the focus of our group's research in HIV for more than seven years. We have discovered that oral epithelial cell-derived beta defensins can: 1) be induced by HIV; 2) inhibit the ability of the virus to infect immunocompetent cells; and 3) interact with specific chemokine and toll-like receptors resulting in regulation of adaptive immune cells. Moreover, chronic HIV infection and/or highly active antiretroviral therapy (HAART) predisposes the oral mucosae to both cellular and innate immune impairment. Interestingly, amongst the repertoire of innate immune molecules, hBDs are unique, as copy number variations have only been reported for the beta defensin gene cluster; possibly explaining the interpersonal variability in hBD expression levels. Our multidisciplinary program is synergistic through the direct collaboration and interaction of our faculty and core facilities that will support the projects. Investigators in Project 1 and Project 2 will cooperatively design, produce, and share altered forms of beta defensin molecules that will be utilized in structure/function studies in both projects that explore defensin interactions with chemokine and toll-like receptors. Investigators from Projects 1 and 3 will utilize expertise in immunology and dermatology to design and implement studies that explore the cross-talk between epithelial cells and antigen presenting cells. Projects 3 and 4 will share tissue isolated from oral warts and other oral mucosal complication associated with HIV to examine their protein and genomic profiles. Thus, these projects are highly integrated on both a theoretical and collaborative basis and involve a multidisciplinary approach that includes expertise in defensin biology, structural chemistry, HIV immunology, dermatology and genetics. Finally, projects will be supported by the Proteomics and Biostatistics Core (Core B), and information gathered through the Program Project will be examined so that the sum of the data may generate overarching conclusions regarding our central hypothesis. All the data will be subjected to rigorous scientific scrutiny through meetings between the PIs and an External Advisory Panel that will be organized through the Administrative Core (Core A).

描述（由申请人提供）：有感染艾滋病毒风险的弱势群体包括少数民族。虽然非洲裔美国人占美国人口的13%，但他们占艾滋病毒/艾滋病新诊断的一半左右。自2000年以来，一些报告表明，口服HPV生长在HAART的艾滋病毒/艾滋病患者中正在增加，并且这种情况在弱势人群中更为普遍，例如非洲裔美国人而不是白人。这个项目的中心假设是先天防御机制的改变决定了HIV感染后口腔并发症的易感性。人类β防御素（hBD）一直是我们小组在HIV研究中的重点，已有七年多的时间。我们已经发现，口腔上皮细胞衍生的β防御素可以：1）由HIV诱导; 2）抑制病毒感染免疫活性细胞的能力;和3）与特异性趋化因子和toll样受体相互作用，导致适应性免疫细胞的调节。此外，慢性HIV感染和/或高效抗逆转录病毒疗法（HAART）使口腔粘膜易于发生细胞和先天免疫损伤。有趣的是，在先天免疫分子的库中，hBD是独特的，因为拷贝数变化仅被报道用于β防御素基因簇;这可能解释了hBD表达水平的人际变异性。我们的多学科计划是通过我们的教师和核心设施，将支持项目的直接合作和互动协同。项目1和项目2的研究人员将合作设计，生产和分享β防御素分子的改变形式，这些分子将用于两个项目的结构/功能研究，探索防御素与趋化因子和Toll样受体的相互作用。项目1和3的研究人员将利用免疫学和皮肤病学的专业知识设计和实施研究，探索上皮细胞和抗原呈递细胞之间的相互作用。项目3和4将分享从口腔疣和其他与艾滋病毒相关的口腔粘膜并发症中分离的组织，以检查其蛋白质和基因组图谱。因此，这些项目在理论和合作基础上高度整合，涉及多学科方法，包括防御素生物学，结构化学，艾滋病毒免疫学，皮肤病学和遗传学的专业知识。最后，项目将得到蛋白质组学和生物统计学核心（核心B）的支持，并将检查通过计划项目收集的信息，以便数据的总和可以产生关于我们的中心假设的总体结论。所有数据都将通过PI与外部咨询小组之间的会议进行严格的科学审查，该咨询小组将通过行政核心（核心A）组织。