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体或人群水平上可能有很大差异。为了阐明宿主因子调节对HIV-1感染的可变反应的作用，伯明翰亚拉巴马大学医学副教授唐建明博士建议测试早期和正在进行的研究产生的几个假设。这项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），CD 8 + CD 38 + T细胞百分比（T细胞活化）和CD 4 + T细胞计数（免疫缺陷）记录。高灵敏度，ELISA为基础的分析将被用来同时定量血浆水平的16个细胞因子和趋化因子在未经治疗的患者;产品是明确相关的对比HIV-1相关的结果将在患者进行有效的抗逆转录病毒治疗前后进行评估。此外，编码信息性细胞因子、趋化因子和相关产物（例如，受体）将被靶向用于单核苷酸多态性（SNP）的高密度、基于微珠阵列的基因分型，并通过TaqMan SNP测定和选择性再测序进行补充和完善。将在多变量模型中检测与HIV-1相关结局或全身细胞因子/趋化因子表达的遗传关联的独立和潜在交互作用。相同的SNP数据集可以分析与青少年队列中常见的另外两种病原体（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相关性。总体而言，这些多方面的分析，沿着与二次（确证性）工作的基础上研究120例成人慢性HIV-1感染，预计将允许宝贵的培训，生物统计学的应用，并提供一个强大的帐户异质性细胞因子对HIV-1感染的反应。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，重点是免疫受损宿主的感染和免疫。

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.