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.

大多数慢性HIV感染者都会经历免疫系统的严重失调。长寿的记忆B细胞消失，而未成熟的B细胞过度活化，产生大量无效的免疫球蛋白。此外，作为HIV主要靶点的CD 4细胞在感染的慢性期会持续下降。大约10-20%的HIV感染者克服或逃避这种广泛的免疫功能障碍，并产生广泛中和的HIV抗体。了解这些个体如何产生广泛中和的HIV抗体对于HIV疫苗的开发至关重要。 我们假设，H1 V+精英中和剂有一个较少的破坏B淋巴细胞室和/或增强的滤泡辅助CD 4 T淋巴细胞的人口相比，平均或中和性差的个人。将通过在感染后两个早期和两个晚期时间点对B和T淋巴细胞群进行多参数流式细胞术分析，比较产生广泛中和抗体的个体与中和剂一般/较差的个体和未感染个体，来检验这一假设。B淋巴细胞分化为抗体分泌细胞的能力和滤泡性T辅助细胞的能力 还将在精英和中和性差的个体中比较CD 4细胞产生重要的辅助细胞因子（如IL-4和IL-21）的能力。这些发现将有助于确定精英中和剂如何产生有用的HIV抗体，并可能大大有助于开发有效的HIV疫苗。