Heterogeneity in Cytokine Responses to HIV-1 Infection

描述（由申请人提供）：自然和治疗的人类免疫缺陷病毒1型（HIV-1）感染的免疫学和临床表现在个人或群体水平上有很大差异。为了阐明宿主因子在调节对HIV-1感染的可变反应中的作用，伯明翰阿拉巴马大学医学副教授唐建明博士提议测试早期和正在进行的研究产生的几个假设。该研究将检查关键的细胞因子和趋化因子途径，这些有希望的初步数据共同指出它们在HIV-1感染的免疫发病机制中的重要性。主要工作将依赖于530名青少年的历史队列，其结果已经通过纵向（季度）测量病毒载量（病毒-宿主平衡），CD8+CD38+ t细胞百分比（t细胞激活）和CD4+ t细胞计数（免疫缺陷）记录。高灵敏度、基于elisa的检测将用于同时定量16种细胞因子和趋化因子在未治疗患者中的血浆水平；那些与hiv -1相关结果明显相关的产品将在有效抗逆转录病毒治疗前后的患者中进行评估。此外，编码信息细胞因子、趋化因子和相关产物（如受体）的基因将成为高密度、基于头阵列的单核苷酸多态性（SNP）基因分型的目标，并通过TaqMan SNP检测和选择性重测序进行补充和完善。将在多变量模型中测试与hiv -1相关结果或全身细胞因子/趋化因子表达的遗传关联，以确定其独立和潜在的相互作用。同样的SNP数据集可以分析与青少年队列中常见的另外两种媒介（沙眼衣原体和单纯疱疹病毒2型）引起的性传播感染的遗传关联。总的来说，这些多方面的分析，以及基于对120名慢性HIV-1感染成人的研究的二次（确证性）工作，有望在生物统计学应用方面提供有价值的培训，并提供对HIV-1感染的异质细胞因子反应的有力解释。这项工作中最具说服力和普遍性的发现应该为唐博士进行有针对性的实验研究铺平道路，并大大加强合作研究计划，重点关注免疫功能低下宿主的感染和免疫。

DESCRIPTION (provided by applicant): Immunological and clinical manifestations of natural and treated human immunodeficiency virus type 1 (HIV-1) Infection can vary considerably at the individual or population level. To elucidate the role of host factors that regulate variable responses to HIV-1 infection, Dr. Jianming Tang, Associate Professor of Medicine at the University of Alabama at Birmingham, proposes to test several hypotheses generated by earlier and ongoing studies. The research will examine critical cytokine and chemokine pathways for which promising preliminary data collectively point to their importance in the immunopathogenesis of HIV-1 infection. The primary work will rely on a historical cohort of 530 adolescents whose outcomes have already been documented through longitudinal (quarterly) measurements of viral load (virus-host equilibrium), CD8+CD38+ T-cell percentage (T-cell activation), and CD4+ T-cell counts (immunodeficiency). Highly sensitive, ELISA-based assays will be used to simultaneously quantify plasma levels of 16 cytokines and chemokines in untreated patients; products that are clearly correlated with contrasting HIV-1-relatedoutcomes will be evaluated in patients before and after effective antiretroviral therapy. In addition, genes encoding informative cytokines, chemokines, and related products (e.g., receptors) will be targeted for high density, bead array-based genotyping of single nucleotide polymorphisms (SNPs), supplemented and refined by TaqMan SNP assays and selective re-sequencing. Genetic associations with HIV-1-relatedoutcomes or systemic cytokine/chemokine expression will be tested for independent and potentially interactive effects in multivariable models. The same SNP dataset can be analyzed for genetic associations with sexually transmitted infections due to two other agents (Chlamydia trachomatis and herpes simplex virus type 2) commonly seen in the adolescent cohort. Overall, these multifaceted analyses, along with secondary (confirmatory) work based on studies of 120 adults with chronic HIV-1 infection, are expected to allow valuable training in biostatistical applications and provide a robust account of heterogeneous cytokine responses to HIV-1 infection. The most convincing and generalizable of findings from this work should pave the way for Dr. Tang to pursue targeted experimental studies and substantially strengthen a collaborative research program that focuses on infection and immunity in immunocompromised hosts.