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: 7339125
• 负责人: Jianming Tang
• 金额: $ 10.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339125
• 关键词: Accounting; Adolescent; Adopted; Adult; Age-Years; 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; day; 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）：自然和治疗的人类免疫缺陷病毒1型（HIV-1）感染的免疫和临床表现可能在个人或人口水平上有很大差异。为了阐明调节对HIV-1感染的可变反应的宿主因素的作用，阿拉巴马大学伯明翰大学医学副教授Jianming Tang博士建议检验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，为此，有希望的初步数据共同指出了它们在HIV-1感染的免疫发病发生中的重要性。主要工作将依靠530名青少年的历史人群，其结果已经通过纵向（季度）病毒载荷（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）进行了记录。高度敏感的基于ELISA的测定将用于同时量化未治疗患者的16个细胞因子和趋化因子的血浆水平；在有效的抗逆转录病毒疗法之前和之后，将评估与与HIV-1相关的对比明显相关的产品。此外，编码信息性细胞因子，趋化因子及相关产物（例如受体）的基因将针对高密度，基于珠阵列的基于珠阵列的基因分型（SNP），并补充了Taqman SNP分析和精选的基因。与HIV-1相关的OutOutcomes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进行独立且潜在的互动效应。可以分析相同的SNP数据集，以分析由于青少年队列中常见的另外两种药物（衣原体沙眼和单纯疱疹病毒2）而引起的与性传播感染的遗传关联。总体而言，这些多面分析以及基于对120名慢性HIV-1感染的成年人的研究（验证）工作，预计将允许在生物统计应用中进行有价值的训练，并提供对HIV-1感染异质细胞因子反应的强有力解释。这项工作中最有说服力和最具普遍性的发现，应该为Tang博士提供有针对性的实验研究的道路，并实质上加强了一项协作研究计划，该计划侧重于免疫功能低下的宿主感染和免疫力。