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: 7488548
• 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/7488548
• 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)：自然感染和治疗后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人或人群水平上可能有很大差异。为了阐明宿主因素在调节对HIV-1感染的不同反应中的作用，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由早期和正在进行的研究产生的几个假说。这项研究将检查关键的细胞因子和趋化因子途径，对于这些途径，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。初步工作将依赖于530名青少年的历史队列，他们的结果已经通过纵向(季度)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+T细胞计数(免疫缺陷)来记录下来。高灵敏度的、基于ELISA的分析将被用来同时量化未经治疗的患者的16种细胞因子和趋化因子的血浆水平；与艾滋病毒-1相关的明显相关的产品将在有效的抗逆转录病毒治疗前后对患者的预后进行评估。此外，编码信息性细胞因子、趋化因子和相关产物(如受体)的基因将被定位于高密度、基于珠阵列的单核苷酸多态(SNPs)基因分型，并通过TaqMan SNP分析和选择性重新测序进行补充和精炼。与HIV-1相关结局或全身性细胞因子/趋化因子表达的遗传关联将在多变量模型中测试独立的和潜在的交互影响。同样的SNP数据集可以分析由于另外两种在青少年队列中常见的病原体(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感染成人研究的二次(验证性)工作，预计将允许在生物统计学应用方面进行有价值的培训，并提供对HIV-1感染的不同细胞因子反应的有力说明。这项研究得出的最具说服力和概括性的发现，应该会为唐博士开展有针对性的实验研究铺平道路，并大大加强一个以免疫受损宿主的感染和免疫为重点的合作研究项目。