Immune Response to Pneumococcal Vaccination in HIV Infected Adults

HIV 感染成人对肺炎球菌疫苗的免疫反应

基本信息

批准号：
8089327
负责人：
M.A. Julia WESTERINK
金额：
$ 36.73万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089327
关键词：
2 year old Adult Affect Affinity Anti-Idiotypic Antibodies Antibodies Antibody Affinity Antibody Formation Antigens B cell differentiation B-Lymphocyte Subsets B-Lymphocytes Biological Assay CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cell Culture Techniques Cell Separation Clinical Diagnosis Enzyme-Linked Immunosorbent Assay Functional disorder Gene Family Genes HIV HIV Envelope Protein gp120 Highly Active Antiretroviral Therapy Immune Immune response Immunization Immunoglobulin G Immunoglobulin M Immunosuppression Incidence Individual Light Link Lymphocyte Count Measures Memory Memory B-Lymphocyte Molecular Molecular Structure Nature Newly Diagnosed Outcome Study Persons Pneumococcal Infections Pneumococcal vaccine Polysaccharides Polyvalent pneumococcal vaccine Population Proteins Recommendation Serological Serum Sorting - Cell Movement Specificity Staging Streptococcus pneumoniae Study Subject Surface Plasmon Resonance Techniques Testing Time Vaccinated Vaccination Vaccine Antigen Vaccines Viral Viral Proteins Virus Diseases base human monoclonal antibodies novel pathogen public health relevance reconstitution respiratory response

项目摘要

DESCRIPTION (provided by applicant): Streptococcus pneumoniae is the most common bacterial respiratory pathogen in human immunodeficiency virus (HIV)-infected individuals. Although vaccination with the pneumococcal polysaccharide vaccine (PPV) is recommended for all those >2 years of age infected with HIV, the response to the vaccine is less than optimal and correlates with the degree of immune suppression as measured by CD4+ T-lymphocyte count (1-10). In addition, vaccine recommendations in newly diagnosed HIV-positive persons with CD4 counts <200 and those concerning revaccination after 5 years are controversial as there is no evidence to confirm clinical or serological benefit. The poor immune response to vaccine antigens is likely related to the severe B cell dysfunction noted early in HIV disease. The viral protein, gp120, acts as a super-antigen restricted to recognition of the variable heavy chain 3 (VH3) gene segments (11). Moreover, gp120 activates proliferation and differentiation of B cells expressing the VH3 gene (11-14) resulting in progressive deletion of VH3- expressing B cells (15). Depletion of the VH3 expressing B cell population is highly significant as the VH3 gene family products encode >90% of anti-pneumococcal polysaccharide (PPS) antibodies (16-20). However, a comprehensive study, directly linking anti-PPS antibody levels, functionality and molecular structure/gene family usage has not been performed. We have modified a novel technique of single antigen-specific B cell isolation/culture allowing analysis of paired variable heavy (VH) and variable light (VL) gene usage and successfully applied this technique to PPS-specific B cells. In addition, we have recently developed a flow analysis technique that allows us to define the B cell subsets of PPS-responding B cells. This unique ability allows us to define the presence of memory B cells amongst PPS-responding B cell populations in HIV-negative, HIV-positive HAART-naive and HIV-positive HAART-treated populations. We therefore propose to perform a comprehensive study of the immune response to PPV in HIV-positive individuals. In Specific Aim 1, we propose to define the immune response to PPV in various stages of untreated HIV infection on a quantitative, functional and molecular level, using a novel, single antigen-specific B cell isolation and culture technique. In Specific Aim 2, we will test the hypothesis that individuals on long-term HAART therapy are capable of responding to the pneumococcal vaccine and investigate the nature of this response. In Specific Aim 3, we will study the percentage of PPS-specific B cells that are IgM or switched memory B cells in the HIV- negative population and compare this to HIV-positive, HAART-naive and HIV-positive HAART-treated population following primary vaccination with PPV. The proposed studies are thus unique, as they will provide a comprehensive picture of the immune response to PPV in the HAART-naive and HAART-treated HIV-positive populations. More importantly, the results of these studies could clarify controversies in the present vaccine recommendations in the HIV-infected population. PUBLIC HEALTH RELEVANCE: The proposed studies are thus unique as they will provide a comprehensive picture of the immune response to PPV in the HAART-naive and HAART-treated HIV-positive populations. More importantly, the results of these studies could clarify controversies in the present vaccine recommendations in the HIV-infected population.

描述（由申请人提供）：肺炎链球菌是人类免疫缺陷病毒（HIV）感染者中最常见的细菌性呼吸道病原体。尽管建议所有 2 岁以上感染 HIV 的人接种肺炎球菌多糖疫苗 (PPV)，但对疫苗的反应并不理想，并且与通过 CD4+ T 淋巴细胞计数测量的免疫抑制程度相关。 1-10）。此外，对于新诊断的 CD4 计数<200 的 HIV 阳性患者的疫苗建议以及有关 5 年后重新接种疫苗的建议存在争议，因为没有证据证实临床或血清学益处。对疫苗抗原的不良免疫反应可能与 HIV 疾病早期发现的严重 B 细胞功能障碍有关。病毒蛋白 gp120 作为超级抗原，仅限于识别可变重链 3 (VH3) 基因片段 (11)。此外，gp120 激活表达 VH3 基因的 B 细胞的增殖和分化 (11-14)，导致表达 VH3 的 B 细胞逐渐缺失 (15)。表达 VH3 的 B 细胞群的消耗非常重要，因为 VH3 基因家族产物编码 > 90% 的抗肺炎球菌多糖 (PPS) 抗体 (16-20)。然而，尚未进行直接将抗 PPS 抗体水平、功能和分子结构/基因家族使用联系起来的全面研究。我们改进了一种单抗原特异性 B 细胞分离/培养的新技术，允许分析配对的可变重链 (VH) 和可变轻链 (VL) 基因的使用情况，并成功将该技术应用于 PPS 特异性 B 细胞。此外，我们最近开发了一种流式分析技术，使我们能够定义 PPS 反应 B 细胞的 B 细胞亚群。这种独特的能力使我们能够确定 HIV 阴性、HIV 阳性未接受过 HAART 治疗的人群和 HIV 阳性 HAART 治疗人群中 PPS 反应 B 细胞群中记忆 B 细胞的存在情况。因此，我们建议对 HIV 阳性个体对 PPV 的免疫反应进行全面研究。在具体目标 1 中，我们建议使用一种新型的单抗原特异性 B 细胞分离和培养技术，在定量、功能和分子水平上定义未经治疗的 HIV 感染各个阶段对 PPV 的免疫反应。在具体目标 2 中，我们将检验长期 HAART 治疗的个体能够对肺炎球菌疫苗产生反应的假设，并调查这种反应的性质。在具体目标 3 中，我们将研究 HIV 阴性人群中 PPS 特异性 B 细胞（IgM 或转换记忆 B 细胞）的百分比，并将其与 HIV 阳性、未接受过 HAART 治疗的人群以及 HIV 阳性接受过 HAART 治疗的人群进行比较，如下：初次接种 PPV。因此，拟议的研究是独一无二的，因为它们将提供未接受过HAART和接受过HAART治疗的HIV阳性人群对PPV免疫反应的全面了解。更重要的是，这些研究的结果可以澄清目前针对艾滋病毒感染人群的疫苗建议中存在的争议。公共卫生相关性：因此，拟议的研究是独一无二的，因为它们将全面了解未经 HAART 治疗和接受过 HAART 治疗的 HIV 阳性人群对 PPV 的免疫反应。更重要的是，这些研究的结果可以澄清目前针对艾滋病毒感染人群的疫苗建议中存在的争议。