Mechanisms of Impaired HIV-associated B cell and Pneumococcal Vaccine responses

HIV 相关 B 细胞和肺炎球菌疫苗反应受损的机制

基本信息

批准号：
8659163
负责人：
Edward N Janoff
金额：
$ 54.37万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8659163
关键词：
AIDS/HIV problem Adult Affinity Agonist Anti-Retroviral Agents Antibodies Antibody Formation Architecture Autoimmune Diseases Avidity B Cell Proliferation B-Cell Activation B-Cell Lymphomas B-Lymphocyte Subsets B-Lymphocytes BCL6 gene Bacteremia Bacteria Bacterial Pneumonia Binding Cause of Death Cell Maturation Cell Nucleus Cell physiology Cells Clinical Complementarity Determining Regions Cytoplasmic Protein DNA Defect Development Disease Enzyme Activation Enzyme-Linked Immunosorbent Assay Flow Cytometry Frequencies Functional disorder Genes Goals HIV HIV Infections HIV vaccine Helper-Inducer T-Lymphocyte Image Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Constant Region Immunoglobulin G Immunoglobulin M Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulin Variable Region Immunoglobulin-Secreting Cells In Vitro Incidence Infection Infection Control Infection prevention Learning Lymphoid Lymphoid Tissue Malignant Neoplasms Memory Memory B-Lymphocyte Messenger RNA Modeling Molecular Mutation Organism Outcome Patients Persons Pharmaceutical Preparations Phenotype Plasma Pneumococcal Infections Pneumococcal Pneumonia Pneumococcal vaccine Polysaccharides Preventive Process Production Proteins RNA Receptors, Antigen, B-Cell Regulation Role Serum Site Stimulus Streptococcus pneumoniae Structure of germinal center of lymph node T-Cell Activation T-Lymphocyte TCF Transcription Factor Time Vaccination Vaccines Virus activation-induced cytidine deaminase antigen binding antiretroviral therapy capsule clinical efficacy crosslink design enzyme linked immunospot assay fighting immune function in vivo killings mRNA Expression pathogen prevent public health relevance response secondary infection

项目摘要

DESCRIPTION: HIV-associated B cell defects are associated with an increased incidence of secondary infections, autoimmune disease and B cell lymphomas. High rates of infection, such as pneumococcal pneumonia and bacteremia, and poor responses to preventive vaccines among persons with HIV infection, even with antiretroviral therapy, may be related to an impaired ability of B cells to generate antibodies of sufficient quantity, quality and function to control these pathogens. The development of effective antibodies requires mutations in the antigen-binding hypervariable region to enhance binding to pathogens as well as changes in the conserved constant regions (switch from IgM to IgG or IgA) to enhance killing of organisms. Both of these effects are controlled by a pivotal molecule, activation-induced cytidine deaminase (AID), in B cells in inductive sites in lymphoid tissue, the germinal centers (GC). HIV infection can have dramatic detrimental effects on the architecture and function of germinal centers as well as on B cells themselves. The consequence is the production of antibodies in low concentrations and with limited protective activity. We propose to study B cell abnormalities in patients with HIV infection and control adults by characterizing B cell phenotype by multiparameter flow cytometry, expression, regulation and function of AID to support B cells in response to model stimuli in vitro as well as with in vivo challenge with pneumococcal vaccines. We utilize clinical, cellular and molecular approaches to understanding B cell defects during HIV infections and vaccines in the context of evaluating the potential protection afforded by the antibodies they elicit as well as in their role as controlled and targeted probes of integrated immune function.

描述：HIV 相关 B 细胞缺陷与继发感染、自身免疫性疾病和 B 细胞淋巴瘤发病率增加有关。肺炎球菌肺炎和菌血症等高感染率，以及 HIV 感染者即使接受抗逆转录病毒治疗，对预防性疫苗的反应也较差，可能与 B 细胞产生足够数量、质量和功能的抗体的能力受损有关。控制这些病原体。有效抗体的开发需要抗原结合高变区的突变以增强与病原体的结合，以及保守恒定区的变化（从 IgM 转换为 IgG 或 IgA）以增强对生物体的杀伤力。这两种效应均由淋巴组织（生发中心 (GC)）诱导位点的 B 细胞中的关键分子（激活诱导的胞苷脱氨酶 (AID)）控制。 HIV 感染会对生发中心以及 B 细胞本身的结构和功能产生巨大的有害影响。其结果是产生低浓度且保护活性有限的抗体。我们建议通过多参数流式细胞仪表征 B 细胞表型、AID 的表达、调节和功能来研究 HIV 感染患者和对照成人的 B 细胞异常，以支持 B 细胞对体外模型刺激以及体内挑战的反应与肺炎球菌疫苗。我们利用临床、细胞和分子方法来了解 HIV 感染和疫苗期间的 B 细胞缺陷，评估它们引发的抗体提供的潜在保护以及它们作为综合免疫功能的受控和靶向探针的作用。