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

• 批准号: 8461897
• 负责人: M.A. Julia WESTERINK
• 金额: $ 34.85万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 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/8461897
• 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

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.

描述（由申请人提供）：肺炎链球菌是人类免疫缺陷病毒（HIV）感染的个体中最常见的细菌呼吸道病原体。尽管建议对所有感染HIV感染的2岁的肺炎球菌多糖疫苗（PPV）进行疫苗接种，但对疫苗的反应小于最佳，并且与通过CD4+ T- lymphopymphopyteter Count（1-10）所测量的免疫抑制程度相关。此外，在新诊断的CD4计数<200的新诊断的HIV阳性患者中的疫苗建议和5年后有关重新接种的疫苗建议是有争议的，因为没有证据可以确认临床或血清学益处。对疫苗抗原的免疫反应差可能与HIV疾病早期注意到的严重B细胞功能障碍有关。病毒蛋白GP120充当一种超抗原，仅限于识别可变重链3（VH3）基因段（11）。此外，GP120激活表达VH3基因的B细胞的增殖和分化（11-14），从而导致VH3-表达B细胞的进行性缺失（15）。 VH3表达B细胞群的耗竭非常显着，因为VH3基因家族产物编码> 90％的抗巨摄是多糖（PPS）抗体（16-20）。然而，一项全面的研究，即直接连接抗PPP抗体水平，功能和分子结构/基因家族使用率。我们已经修改了一种新型的单抗原特异性B细胞分离/培养技术，以分析配对的可变重（VH）和可变光（VL）基因使用，并成功地将此技术应用于PPS特异性B细胞。此外，我们最近开发了一种流动分析技术，该技术使我们能够定义PPS响应B细胞的B细胞子集。这种独特的能力使我们能够在HIV阴性，HIV阳性HAART-NEIVE和HIV阳性HAART治疗群体中定义PPS响应B细胞种群中记忆B细胞的存在。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。在特定目标1中，我们建议使用一种新型的，单一的抗原特异性B细胞分离和培养技术来定义未经处理的HIV感染的各个阶段的免疫反应。在特定目标2中，我们将检验以下假设：长期HAART治疗的个体能够对肺炎球菌疫苗有反应并研究这种反应的性质。在特定的目标3中，我们将研究HIV-PANT-DEAM-B-B细胞的PPS特异性B细胞的百分比，它们是HIV - 阴性人群中的IgM或切换的记忆B细胞的百分比，并将其与HIV阳性，HAART-NEAVE和HIV阳性HAART HAART治疗的HAART HAART治疗种群进行了比较。因此，拟议的研究是独一无二的，因为它们将提供有关HAART-NAIVE和HAART处理的HIV阳性人群中对PPV的免疫反应的全面图片。更重要的是，这些研究的结果可以阐明艾滋病毒感染人群的当前疫苗建议中的争议。

项目成果

Alterations in serotype-specific B cell responses to the 13-valent pneumococcal conjugate vaccine in aging HIV-infected adults.

在老年 HIV 感染者中，血清型特异性 B 细胞对 13 价肺炎球菌结合疫苗的反应发生变化。

• DOI: 10.1016/j.vaccine.2015.12.013
• 发表时间: 2016
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Ohtola,JenniferA;Khaskhely,NoorM;Saul-Mcbeth,JessicaL;Iyer,AnitaS;Leggat,DavidJ;Khuder,SadikA;Westerink,MAJulie
• 通讯作者: Westerink,MAJulie

Response to Pneumococcal Polysaccharide Vaccination in HIV-Positive Individuals on Long Term Highly Active Antiretroviral Therapy.

接受长期高效抗逆转录病毒治疗的 HIV 阳性个体对肺炎球菌多糖疫苗的反应。

• DOI: 10.4172/2155-6113.1000421
• 发表时间: 2015
• 期刊: Journal of AIDS & clinical research
• 作者: Iyer,AnitaS;Leggat,DavidJ;Ohtola,JenniferA;Duggan,JoanM;Georgescu,ClaudiuA;AlRizaiza,AdeebA;Khuder,SadikA;Khaskhely,NoorM;Westerink,Julie
• 通讯作者: Westerink,Julie

Quantitative and Functional Antibody Responses to the 13-Valent Conjugate and/or 23-Valent Purified Polysaccharide Vaccine in Aging HIV-Infected Adults.

老年 HIV 感染者对 13 价缀合物和/或 23 价纯化多糖疫苗的定量和功能性抗体反应。

• DOI: 10.4172/2155-6113.1000556
• 发表时间: 2016
• 期刊: Journal of AIDS & clinical research
• 作者: Ohtola,JenniferA;Saul-McBeth,JessicaL;Iyer,AnitaS;Leggat,DavidJ;Khuder,SadikA;Khaskhely,NoorM;Westerink,MaJulie
• 通讯作者: Westerink,MaJulie