Heterogeneity in Cytokine Responses to HIV-1 Infection

HIV-1 感染的细胞因子反应的异质性

• 批准号: 7919719
• 负责人: Jianming Tang
• 金额: $ 4.94万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919719
• 关键词: 19 year old; Accounting; Adolescent; Adopted; Adult; Alabama; Biological Assay; Biotechnology; CD4 Positive T Lymphocytes; CXCL12 gene; Candidate Disease Gene; Cell Count; Cell physiology; Chlamydia; Chlamydia trachomatis; Chronic; Clinical; Cohort Studies; Complex; Data; Data Set; Disease; Enrollment; Ensure; Equilibrium; Funding; Genes; Genetic Variation; Genital system; Genotype; Goals; Grant; HIV; HIV-1; Healthcare; Heterogeneity; Human; Human Genetics; Human Herpesvirus 2; Immune; Immunity; Immunocompromised Host; Immunogenetics; Immunologic Deficiency Syndromes; Individual; Individual Differences; Infection; Influentials; Integration Host Factors; Interleukin-10; Interleukin-15; Interleukin-7; Interleukins; Ligands; Measures; Medicine; Memory; Modeling; National Institute of Allergy and Infectious Disease; Outcome; Pathogenesis; Pathway interactions; Patients; Plasma; Population; Proteins; RANTES; Research; Role; Sexually Transmitted Diseases; Single Nucleotide Polymorphism; Staining method; Stains; Stromal Cell-Derived Factor 1; T-Cell Activation; T-Lymphocyte; Techniques; Technology; Testing; Time; Training; Universities; Variant; Viral load measurement; Virus; Work; antiretroviral therapy; base; chemokine; cohort; cytokine; density; genetic association; insight; member; nuclease; professor; programs; receptor; reconstitution; research study; response

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.

描述（由申请人提供）：自然和治疗后的 1 型人类免疫缺陷病毒 (HIV-1) 感染的免疫学和临床表现在个体或群体水平上可能存在很大差异。为了阐明调节 HIV-1 感染不同反应的宿主因素的作用，阿拉巴马大学伯明翰分校医学副教授唐建明博士建议检验早期和正在进行的研究中产生的几个假设。该研究将检查关键的细胞因子和趋化因子途径，有希望的初步数据共同表明它们在 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，这些青少年的结果已通过病毒载量（病毒-宿主平衡）、CD8+CD38+ T 细胞百分比（T 细胞激活）和 CD4+ 的纵向（季度）测量记录下来。 T 细胞计数（免疫缺陷）。基于 ELISA 的高灵敏度检测将用于同时量化未经治疗患者的 16 种细胞因子和趋化因子的血浆水平；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，编码信息性细胞因子、趋化因子和相关产物（例如受体）的基因将针对单核苷酸多态性 (SNP) 进行高密度、基于微珠阵列的基因分型，并通过 TaqMan SNP 测定和选择性重测序进行补充和完善。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将在多变量模型中测试独立和潜在的相互作用效应。可以分析同一 SNP 数据集与青少年群体中常见的另外两种病原体（沙眼衣原体和 2 型单纯疱疹病毒）引起的性传播感染的遗传关联。总体而言，这些多方面的分析以及基于 120 名慢性 HIV-1 感染成年人研究的二次（验证性）工作，预计将为生物统计应用提供有价值的培训，并提供对 HIV-1 感染的异质细胞因子反应的可靠说明。这项工作中最令人信服和最普遍的发现应该为唐博士进行有针对性的实验研究铺平道路，并大大加强专注于免疫受损宿主感染和免疫的合作研究计划。