Variation in Immune Activation in HIV-1 Infected Persons

描述（由申请人提供）：HIV-1感染个体之间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，这可能是由入侵病原体、被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（除了血浆HIV-1 RNA水平）。例如，携带低pol复制能力病毒的患者CD4+ T细胞计数升高，尽管病毒复制水平很高，这表明这些变异降低了体内毒力。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细胞激活水平赋予其保护（或有害）作用。

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.