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).

说明(申请人提供)：易感染艾滋病毒的人群包括少数族裔。虽然非裔美国人占美国人口的13%，但他们约占新诊断的艾滋病毒/艾滋病病例的一半。自2000年以来，几份报告表明，接受HAART治疗的艾滋病毒/艾滋病患者的口腔HPV增长正在增加，而且这种情况在脆弱人群中更普遍，例如非裔美国人比白人。该计划项目的中心假设是，先天防御机制的改变决定了艾滋病毒感染后口腔并发症的易感性。七年多来，人类β防御素(HBDS)一直是我们团队在艾滋病毒方面的研究重点。我们发现口腔上皮细胞衍生的β防御素可以：1)被HIV诱导；2)抑制病毒感染免疫活性细胞的能力；3)与特定的趋化因子和Toll样受体相互作用，调节获得性免疫细胞。此外，慢性HIV感染和/或高效抗逆转录病毒治疗(HAART)使口腔粘膜容易受到细胞和先天免疫损害。有趣的是，在所有的先天免疫分子中，hBD是独一无二的，因为拷贝数的变化只在β防御素基因簇中被报道过；这可能解释了hBD表达水平的人际差异。我们的多学科项目通过我们的教职员工和支持项目的核心设施的直接合作和互动而实现协同。项目1和项目2的研究人员将合作设计、生产和共享改变形式的防御素分子，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和项目3的研究人员将利用免疫学和皮肤病学的专业知识来设计和实施探索上皮细胞和抗原呈递细胞之间的串扰的研究。项目3和4将共享从口腔尖锐湿疣和其他与艾滋病毒相关的口腔粘膜并发症中分离出来的组织，以检查它们的蛋白质和基因组图谱。因此，这些项目在理论和协作基础上高度整合，涉及多学科方法，其中包括防御素生物学、结构化学、艾滋病毒免疫学、皮肤学和遗传学方面的专业知识。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，并将审查通过计划项目收集的信息，以便数据总和可以产生关于我们的中心假设的总体结论。所有数据都将通过私人投资机构和将通过行政核心(核心A)组织的外部咨询小组之间的会议接受严格的科学审查。