Variation in Immune Activation in HIV-1 Infected Persons

HIV-1 感染者免疫激活的变化

• 批准号: 7240428
• 负责人: Jason David Barbour
• 金额: $ 12.18万
• 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/7240428
• 关键词: Variation; Immune; Activation; HIV; Infected; Variation; Immune; Activation; HIV; Infected

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）：感染HIV-1的个体疾病进展率变化的基础尚不清楚，但似乎与异常的T细胞激活水平有关，T细胞激活水平可能取决于入侵病原体，感染宿主及其相互作用的特征。最近的发现表明，病毒生命周期的特征是临床进展的重要相关性（除了血浆HIV-1 RNA水平）。例如，尽管大量的病毒复制水平，表明这些变异降低了体内毒力，但具有低pol复制能力病毒的患者的CD4+ T细胞计数升高。此外，病毒基因组的其他高度可变特征（例如Env和GAG）可能通过T细胞激活调节确定毒力。最后，宿主决定因素（例如HLA类型）与疾病进展的变化有关，并可能通过调节T细胞激活水平来赋予其保护性（或有害）效果。 为了研究HIV-1个体疾病进展率变化的基础，我将使用来自最近感染的个体和长期感染的个体的两个正在进行的同类群的数据进行横截面和纵向分析，这些数据将用于HLA类型，病毒基因型（ENV，GAG，POL），病毒pol Pol重复能力和T细胞活化测量。我将确定对HIV-1感染的免疫激活反应变异反应（AIM 1），HIV-1感染中免疫激活的病毒遗传决定因素（AIM 2）的宿主HLA I和II类遗传预测因子（AIM 2），如果低POL RC病毒与低T细胞活化有关（AIM 3）。通过确定激活的重要调节剂，我们可以确定干预措施以降低T细胞激活水平。为了实现这些目的，我组建了一个国际认可的科学家的指导委员会，在临床调查，免疫发育生成和生物统计学研究中具有强大的记录记录。这些指导者涵盖了几个相关学科，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（McCune和Nixon博士）。他们的指导将有助于我实现在定量转化研究方面发展独立职业的目标，重点是确定HIV-1发病机理的关键要素。