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.

自然和治疗的人类免疫缺陷病毒1型（HIV-1）的免疫学和临床表现 1)在个人或群体水平上，感染可能有很大差异。阐明宿主因子的作用 调节对HIV-1感染的可变反应， 位于伯明翰的亚拉巴马大学提出了几个假设， 正在进行的研究。这项研究将检查关键的细胞因子和趋化因子途径， 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。的 主要工作将依赖于530名青少年的历史队列，其结果已经 通过病毒载量（病毒-宿主平衡）的纵向（季度）测量记录， 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）。高度 将使用灵敏的基于ELISA的测定法同时定量16种细胞因子的血浆水平， 未治疗患者的趋化因子;与对照HIV-1相关 将在有效的抗逆转录病毒治疗前后对患者的结果进行评估。此外，基因 编码信息性细胞因子、趋化因子和相关产物（例如，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， 通过TaqMan SNP分析和选择性重新测序进行优化。与HIV-1相关的遗传关联 结果或全身性细胞因子/趋化因子表达将被测试用于独立的和潜在的 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 由于另外两种病原体（沙眼衣原体和单纯疱疹）而导致的性传播感染 病毒2型）常见于青少年队列。总的来说，这些多方面的分析，沿着 基于对120名慢性HIV-1感染成年人的研究，预计将 允许在生物统计学应用中进行有价值的培训，并提供异质性细胞因子的可靠解释。 对HIV-1感染的反应。这项工作中最有说服力和最具普遍性的发现， 唐博士进行有针对性的实验研究，并大大加强合作的方式 一项研究计划，重点是免疫受损宿主的感染和免疫力。