Variation in Immune Activation in HIV-1 Infected Persons

描述（由申请方提供）：HIV-1感染者疾病进展率变化的基础尚不清楚，但似乎与异常T细胞活化水平有关，这可能是由入侵病原体、感染宿主及其相互作用的特征决定的。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（除血浆HIV-1 RNA水平外）。例如，携带低pol复制能力的病毒的患者具有升高的CD 4 + T细胞计数，尽管病毒复制水平很高，这表明这些变体具有降低的体内毒力。此外，病毒基因组的其他高度可变特征，如ENV和GAG，可能通过T细胞活化调节决定毒力。最后，宿主决定因素，如HLA类型，与疾病进展的变化相关，并可通过调节T细胞活化水平来赋予其保护（或有害）作用。 为了研究HIV-1感染者疾病进展率变化的基础，我将使用来自两个正在进行的队列的数据进行横断面和纵向分析，这些队列包括近期感染者和慢性感染者，他们将进行HLA类型、病毒基因型（ENV、GAG、POL）、病毒pol复制能力和T细胞活化测量。我将确定宿主HLA I类和II类遗传预测因子对HIV-1感染的免疫活化反应的变异（目标1），HIV-1感染中免疫活化的病毒遗传决定因素（目标2），以及低pol RC病毒是否与较低的T细胞活化相关（目标3）。通过鉴定重要的活化调节剂，我们可以确定干预的靶点，以降低T细胞活化水平。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。这些导师横跨多个相关学科，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和尼克松博士）。他们的指导将帮助我实现在定量导向的转化研究中发展独立职业生涯的目标，重点是确定HIV-1发病机制的关键要素。

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.