Variation in Immune Activation in HIV-1 Infected Persons

描述(由申请人提供)：感染HIV-1的个体之间疾病进展率的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，这可能是由入侵病原体、受感染宿主及其相互作用的特征决定的。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因素(除了血浆HIV-1RNA水平之外)。例如，携带POL复制能力低的病毒的患者，尽管病毒复制水平很高，但CD4+T细胞计数增加，这表明这些变异株降低了体内毒力。此外，病毒基因组的其他高度可变的特征，如ENV和GAG，可能通过T细胞激活调节来决定毒力。最后，宿主决定因素，如HLA型，与疾病进展的变化有关，并可能通过调节T细胞激活水平来发挥其保护(或有害)作用。 为了研究HIV-1感染者疾病进展率变化的基础，我将使用最近感染和长期感染的两个正在进行的队列的数据进行横断面和纵向分析，这些人将接受HLA型、病毒基因型(ENV、GAG、POL)、病毒Poll复制能力和T细胞激活测量。我将确定宿主人类白细胞抗原I类和II类对HIV-1感染的免疫激活反应变异的遗传预测因子(AIM 1)，HIV-1感染中免疫激活的病毒遗传决定因素(AIM 2)，以及低PolRC病毒是否与较低的T细胞激活有关(AIM 3)。通过确定重要的激活调节因子，我们可以确定干预目标，以降低T细胞激活水平。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，这些科学家在临床研究、免疫发病机制和生物统计学研究方面有着良好的记录。这些导师涉及几个相关学科，包括临床研究方法(Hecht和Havlir博士)、生物信息学(西格尔博士)、免疫遗传学(Oksenberg博士)和免疫病理学(McCune和Nixon博士)。他们的指导将帮助我实现我的目标，即在以量化为导向的翻译研究中发展独立的职业生涯，专注于确定HIV-1致病机理的关键要素。

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.