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: 8115523
• 负责人: Jianming Tang
• 金额: $ 5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115523
• 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; immune activation; insight; member; nuclease; professor; programs; receptor; reconstitution; research study; response

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-1infection, 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-1infection. 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-related outcomes 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-related outcomes 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-1infection, are expected to allow valuable training in biostatistical applications and provide a robust account of heterogeneous cytokine responses to HIV-1infection. 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.

天然和治疗后的人类免疫缺陷病毒 1 型（HIV- 1) 感染在个人或群体水平上可能有很大差异。阐明宿主因素的作用 调节对 HIV-1 感染的不同反应，Jianming Tang 博士，医学副教授 阿拉巴马大学伯明翰分校提出检验早期和 正在进行的研究。该研究将检查关键的细胞因子和趋化因子途径，这些途径有希望 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。这 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经 通过病毒载量（病毒-宿主平衡）的纵向（季度）测量记录， CD8+CD38+ T 细胞百分比（T 细胞激活）和 CD4+ T 细胞计数（免疫缺陷）。高度 基于 ELISA 的灵敏检测将用于同时量化 16 种细胞因子和 未经治疗的患者中的趋化因子；与 HIV-1 相关产品明显相关的产品 将在有效抗逆转录病毒治疗之前和之后对患者的结果进行评估。此外，基因 编码信息丰富的细胞因子、趋化因子和相关产品（例如受体）将针对高 密度、基于微珠阵列的单核苷酸多态性 (SNP) 基因分型、补充和 通过 TaqMan SNP 检测和选择性重测序进行改进。与 HIV-1 相关的遗传关联 将测试结果或系统性细胞因子/趋化因子表达的独立性和潜在性 多变量模型中的交互效应。可以分析相同的 SNP 数据集的遗传关联 由另外两种病原体（沙眼衣原体和单纯疱疹病毒）引起的性传播感染 2 型病毒）常见于青少年群体。总的来说，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 允许在生物统计应用中进行有价值的培训，并提供异质细胞因子的可靠说明 对 HIV-1 感染的反应。这项工作中最有说服力和最普遍的发现应该为 唐博士进行有针对性的实验研究并实质性加强合作的途径 专注于免疫受损宿主的感染和免疫的研究计划。