Variation in Immune Activation in HIV-1 Infected Persons

HIV-1 感染者免疫激活的变化

• 批准号: 7086886
• 负责人: Jason David Barbour
• 金额: $ 12.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086886
• 关键词: HIV infections; T lymphocyte; clinical research; disease /therapy duration; genetic markers; genotype; histocompatibility typing; host organism interaction; human immunodeficiency virus 1; human subject; immunogenetics; immunopathology; leukocyte activation /transformation; longitudinal human study; patient oriented research; statistics /biometry; virulence; virus genetics; virus replication

Description (provided by applicant): The basis for variation in disease progression rates among individuals infected with HIV-1 is not well understood, but appears to be related to aberrant T cell activation levels, which are likely determined by features of the invading pathogen, the infected host, and their interaction. Recent findings have suggested that features of the viral lifecycle are important correlates of clinical progression (in addition to plasma HIV-1 RNA level). For example, patients bearing a virus of low pol replication capacity have elevated CD4+ T cell counts, despite substantial levels of viral replication, suggesting that these variants have lowered in vivo virulence. In addition, other highly variable features of the viral genome, such as ENV and GAG, may determine virulence through T cell activation modulation. And lastly, host determinants, such as HLA type, have been associated with variation in disease progression and may confer their protective (or deleterious) effect via modulation of T cell activation level. To investigate the basis for variation in disease progression rates in individuals with HIV-1, I will conduct cross-sectional and longitudinal analyses using data from two ongoing cohorts of recently infected individuals and chronically infected individuals who will be assayed for HLA type, viral genotype (ENV, GAG, POL), viral pol replication capacity, and T cell activation measurements. I will determine host HLA Class I and II genetic predictors of variation in immune activation response to HIV-1 infection (Aim 1), viral genetic determinants of immune activation in HIV-1 infection (Aim 2), and if viruses of low pol RC are associated with lower T cell activation (Aim 3). By identifying important modulators of activation, we can determine targets for intervention to lower T cell activation levels. To achieve these aims, I have assembled a mentoring committee of internationally recognized scientists with strong track records in clinical investigation, immunopathogenesis, and biostatistics research. These mentors span several relevant disciplines, including clinical research methods (Drs. Hecht and Havlir), bioinformatics (Dr. Segal), immunogenetics (Dr. Oksenberg) and immunopathogenesis (Drs. McCune and Nixon). Their mentorship will help me achieve my goal of developing an independent career in quantitatively oriented translational research, focusing on determination of key elements of HIV-1 pathogenesis.

描述（由申请人提供）：HIV-1 感染者疾病进展率差异的基础尚不清楚，但似乎与异常的 T 细胞激活水平有关，而异常的 T 细胞激活水平可能由入侵病原体的特征决定。受感染的宿主及其相互作用。最近的研究结果表明，病毒生命周期的特征是临床进展的重要相关因素（除了血浆 HIV-1 RNA 水平）。例如，携带低聚合复制能力病毒的患者尽管病毒复制水平很高，但 CD4+ T 细胞计数升高，表明这些变体降低了体内毒力。此外，病毒基因组的其他高度可变的特征，例如 ENV 和 GAG，可能通过 T 细胞激活调节来决定毒力。最后，宿主决定簇（例如 HLA 类型）与疾病进展的变化相关，并可能通过调节 T 细胞激活水平来赋予其保护（或有害）作用。 为了调查 HIV-1 感染者疾病进展率变化的基础，我将使用来自最近感染者和慢性感染者的两个持续队列的数据进行横断面和纵向分析，这些人将进行 HLA 类型、病毒基因型检测（ENV、GAG、POL）、病毒 pol 复制能力和 T 细胞激活测量。我将确定 HIV-1 感染免疫激活反应变异的宿主 HLA I 类和 II 类遗传预测因子（目标 1），HIV-1 感染中免疫激活的病毒遗传决定因素（目标 2），以及低 pol RC 病毒是否与 T 细胞活化较低有关（目标 3）。通过识别重要的激活调节剂，我们可以确定降低 T 细胞激活水平的干预目标。为了实现这些目标，我组建了一个由国际公认的科学家组成的指导委员会，他们在临床研究、免疫发病机制和生物统计学研究方面拥有良好的记录。这些导师跨越多个相关学科，包括临床研究方法（Hecht 和 Havlir 博士）、生物信息学（Segal 博士）、免疫遗传学（Oksenberg 博士）和免疫发病机制（McCune 和 Nixon 博士）。他们的指导将帮助我实现在定量转化研究领域发展独立职业的目标，重点是确定 HIV-1 发病机制的关键要素。