Detailed mapping and analysis of the evolution of neutralizing antibody responses

中和抗体反应演变的详细绘图和分析

• 批准号: 8042871
• 负责人: John Christopher Love
• 金额: $ 25.26万
• 依托单位: INTERNATIONAL AIDS VACCINE INITIATIVE
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042871
• 关键词: Antibodies; Antibody Formation; Archives; B-Cell Activation; B-Lymphocytes; Biological Assay; Blood specimen; CD4 Positive T Lymphocytes; Capsid Proteins; Cell Count; Cell Lineage; Cells; Chronic; Chronic Phase; Development; Evolution; Flow Cytometry; Frequencies; Functional disorder; HIV; HIV Infections; HIV vaccine; Human; Hypergammaglobulinemia; Immune; Immune System Diseases; Immune response; Immune system; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunosuppression; In Vitro; Individual; Infection; Interleukin-4; Licensing; Maps; Measures; Memory B-Lymphocyte; Pathology; Patients; Phenotype; Population; Prevalence; Production; Protocols documentation; Resources; Role; Sampling; Science; Serum; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Time; Time Study; Vaccination; Vaccines; Viral Pathogenesis; cohort; cytokine; experience; improved; interest; neutralizing antibody; receptor; vaccine development; virology

Most individuals with chronic HIV infection experience massive dysregulation of the immune system. Longlived memory B cells disappear, while immature B cells are hyperactivated and produce significant quantities of ineffective immunoglobulin. Furthermore, CD4 cells, the primary targets of HIV, steadily decline during the chronic phase of infection. Approximately 10-20% of HIV infected individuals overcome or escape this widespread immune dysfunction and produce broadly neutralizing antibodies to HIV. An understanding of how these indivduals generate broadly neutralizing antibodies to HIV is critical for HIV vaccine development. We hypothesize that H1V+ elite neutralizers have a less disrupted B lymphocyte compartment and/or an enhanced population of follicular helper CD4 T lymphocytes when compared to average or poorly neutralizing individuals. This hypothesis will be tested by multiparameter flow cytometric analysis of B and T lymphocyte populations at two early and two late time points post-infection, comparing indivuals who generate broadly neutralizing antibodies with average/poor neutralizers and uninfected individuals. The ability of B lymphocytes to differentiate into antibody secreting cells and the capacity of follicular T helper CD4 cells to produce important helper cytokines, such as IL-4 and IL-21, will also be compared in elite and poorly neutralizing individuals. These findings will help determine how elite neutralizers generate useful antibodies to HIV, and could greatly assist in the development of an effective HIV vaccine.

大多数患有慢性艾滋病毒感染的人会出现免疫系统的大规模失调。长期的记忆B细胞消失，而未成熟的B细胞过度活化并产生大量无效的免疫球蛋白。此外，CD4细胞（HIV的主要靶标）在慢性感染期间稳步下降。大约10-20％的艾滋病毒感染者克服了或逃脱这种广泛的免疫功能障碍，并产生对HIV的广泛中和抗体。了解这些不可分割的人如何产生对HIV的广泛中和抗体对于HIV疫苗发育至关重要。 我们假设H1V+ Elite中源的B淋巴细胞室和/或与平均中和个体相比相比，B淋巴细胞室和/或卵泡辅助CD4 T淋巴细胞的群体增强。该假设将通过在感染后两个早期和两个晚期的B和T淋巴细胞种群对B和T淋巴细胞种群的多参数流式细胞仪分析进行检验，并比较了不可接受的，这些不可分割的人与平均/较差的中源和未感染的个体产生广泛中和的抗体。 B淋巴细胞分化为抗体分泌细胞的能力和滤泡T助手的能力 CD4细胞生产重要的辅助细胞因子，例如IL-4和IL-21，也将在精英和不良中和个体中进行比较。这些发现将有助于确定精英中源如何产生对HIV的有用抗体，并可以大大帮助开发有效的HIV疫苗。