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

• 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
• 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

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：艾滋病毒相关的B细胞缺陷与继发感染、自身免疫性疾病和B细胞淋巴瘤的发病率增加有关。肺炎球菌肺炎和菌血症等感染率高，艾滋病毒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很差，这可能与B细胞产生足够数量、质量和功能的抗体以控制这些病原体的能力受损有关。有效抗体的开发需要抗原结合高变区的突变以加强与病原体的结合，以及保守恒定区的变化(从IgM转变为Ig G或Ig A)以增强对生物体的杀伤力。这两种作用都是由一种关键分子--激活诱导胞苷脱氨酶(AID)控制的，该分子位于淋巴组织生发中心(GC)的诱导部位。艾滋病毒感染会对生发中心的结构和功能以及B细胞本身产生巨大的有害影响。其结果是产生低浓度的抗体，保护活性有限。我们建议通过多参数流式细胞术分析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细胞在体外对模型刺激的反应以及在体内对肺炎球菌疫苗的攻击。我们利用临床、细胞和分子方法来了解艾滋病毒感染和疫苗期间的B细胞缺陷，评估它们诱导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。