Pathogenesis of HIV and HCV in Hemophilia: HGDS

血友病中 HIV 和 HCV 的发病机制：HGDS

• 批准号: 6653915
• 负责人: EDWARD David GOMPERTS
• 金额: $ 63.05万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-25 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653915
• 关键词: HIV infections; T lymphocyte; cellular immunity; comorbidity; cytokine; enzyme linked immunosorbent assay; genetic polymorphism; genetic susceptibility; hemophilia As; hemophilia B; hepatitis C; host organism interaction; human subject; immune tolerance /unresponsiveness; immunopathology; leukocyte activation /transformation; pathologic process; patient oriented research; virus load; virus replication; virus virus interaction

DESCRIPTION: (provided by the applicant) This study will define host and immune factors that influence HCV and HIV-1 infection. Understanding the immunopathogenesis of HIV-1 is vital to vaccine development and the establishment of new treatment strategies. In addition, HCV infection is recognized as a major worldwide threat with significant implications for HIV-1-coinfected individuals. The specific aims of this application are: 1) to investigate the role of viral specific immunologic responses in controlling HIV-1 and HCV infection, 2) to investigate the relationship between CD4+ and CD8+ cellular activation with HIV-1 viral load, HCV viral load, and HIV-1 clinical progression, 3) to investigate how host genetic factors that modulate the expression of intracellular cytokines affect the levels of HCV RNA, HIV-1 RNA and HIV-1 clinical progression, and 4) to investigate the mechanism by which HCV infection affects HIV-1 clinical progression. This study will utilize biologic specimens stored from participants in the Hemophilia Growth and Development Study (HGDS), a U.S. multi-center natural history study that enrolled subjects between 1989 and 1990 with 7-8 years of follow-up. The HGDS included those who were HCV infected (n=126) and those HIV-1/HCV co-infected (n=207). The first aim will utilize tetramer and ELlSPOT assays on longitudinally collected specimens to determine the relationship between HIV-1 specific responses and the control of viral replication and clinical progression. Similar studies will be performed to test the relationship between HCV-specific responses and HCV viral load in both cohorts. The second aim will determine if cellular activation, as measured by expression of activation markers on longitudinally collected CD4+ and CD8+ cells, is associated with HIV-1 and HCV RNA levels, as well as HIV-1 clinical progression. The third aim will determine if genetic polymorphisms in the promoter region of various Th1 and Th2 cytokines predicts HIV-1 clinical progression, and/or the quantity of inducible intracellular cytokines. The final aim of this study will explore the mechanism underlying recent observations that HCV infection and viral load adversely affect HIV-1 clinical progression. Two potential explanations for these observations will be tested. First, to determine if systemic cellular activation, that may occur in the setting of chronic HCV replication, accounts for the enhanced risk of HIV-1 progression, after controlling for CD4+ cell number and HIV viral load. Second, to explore the possibility that chronic HCV infection, previously shown to occur in the setting of waning HCV-specific immune responses, is associated with down-regulation of HIV-1 specific cellular responses and clinical progression. This study will utilize state-of-the-art technology in a well-characterized cohort to expand the current understanding of host and immune factors that influence viral replication and clinical disease progression.

描述：（由申请人提供）本研究将定义宿主和 影响 HCV 和 HIV-1 感染的免疫因素。了解 HIV-1 的免疫发病机制对于疫苗开发和 制定新的治疗策略。此外，HCV感染是 被认为是一个重大的全球威胁，对 HIV-1 合并感染者。该应用程序的具体目标是：1） 研究病毒特异性免疫反应在控制中的作用 HIV-1和HCV感染，2）研究CD4+和HCV之间的关系 CD8+ 细胞激活与 HIV-1 病毒载量、HCV 病毒载量和 HIV-1 临床进展，3) 研究宿主遗传因素如何调节 细胞内细胞因子的表达影响HCV RNA、HIV-1的水平 RNA 和 HIV-1 临床进展，以及 4) 通过以下方式研究其机制 HCV 感染影响 HIV-1 临床进展。这项研究将 利用血友病生长参与者储存的生物样本 和发展研究（HGDS），一项美国多中心自然历史研究， 1989 年至 1990 年间招募的受试者，并进行了 7-8 年的随访。 HGDS 包括 HCV 感染者 (n=126) 和 HIV-1/HCV 共同感染者 （n=207）。第一个目标将利用四聚体和 ELlSPOT 检测 纵向收集的标本以确定 HIV-1 之间的关系 特异性反应以及病毒复制和临床的控制 进展。将进行类似的研究来测试这种关系 两个队列中 HCV 特异性反应和 HCV 病毒载量之间的关系。第二个 目的将确定细胞激活是否通过表达来测量 纵向收集的 CD4+ 和 CD8+ 细胞上的激活标记是 与 HIV-1 和 HCV RNA 水平以及 HIV-1 临床相关 进展。第三个目标将确定遗传多态性是否存在于 各种Th1和Th2细胞因子的启动子区域预测HIV-1临床 进展和/或诱导型细胞内细胞因子的数量。这 本研究的最终目的是探索最近的机制 HCV 感染和病毒载量对 HIV-1 临床产生不利影响的观察结果 进展。将测试这些观察结果的两种可能的解释。 首先，确定全身细胞激活是否可能发生在 HCV 慢性复制环境导致 HIV-1 风险增加 控制 CD4+ 细胞数量和 HIV 病毒载量后的进展。 其次，探讨慢性HCV感染的可能性，以前 显示发生在 HCV 特异性免疫反应减弱的情况下， 与 HIV-1 特异性细胞反应的下调相关 临床进展。这项研究将利用最先进的技术 特征明确的队列，以扩大当前对宿主和 影响病毒复制和临床疾病的免疫因素 进展。