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The Role of Follicular Helper T Cells in HIV Prime Boost Vaccination

滤泡辅助 T 细胞在 HIV 加强疫苗接种中的作用

基本信息

批准号：
8875819
负责人：
Alexander L Dent
金额：
$ 60.25万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8875819
关键词：
ALVAC Affect Affinity Antibodies Antibody Formation Antigens B-Lymphocytes Blood CD4 Positive T Lymphocytes Cells DNA Data Development Drug Formulations Elements Evolution Fostering Frequencies Genes Genetic Variation Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Health Helper-Inducer T-Lymphocyte Human Immune Immunization Immunoglobulin Somatic Hypermutation Immunological Models Infection Knowledge Laboratories Life Measures Memory Modeling Mus Patients Plasma Cells Plasmids Poxviridae Process Production Property Proteins Reaction Recombinant Proteins Recombinants Regulatory T-Lymphocyte Research Role Secondary Immunization Structure of germinal center of lymph node System T-Lymphocyte T-Lymphocyte Subsets Testing Vaccinated Vaccination Vaccines Viral Viral Vector Work base design env Gene Products immunogenicity neutralizing antibody next generation novel plasmid DNA prevent response transmission process vaccine evaluation viral DNA

项目摘要

DESCRIPTION: A major goal towards preventing the transmission of Human Immunodeficiency Virus type-1 (HIV-1) is the development of a broadly protective vaccine. However, this goal has been elusive due to the extreme genetic diversity of HIV-1 and poor immunogenicity of HIV-1 Env antigens. One key element of an effective protective HIV-1 vaccine is broadly neutralizing antibodies (bnAbs) that can block the infection of a diverse group of primary HIV-1 viral isolates. While bnAbs have been identified from HIV-infected patients, the problem of how to induce bnAbs through vaccination has persisted. Lately, the heterologous prime-boost approach, where the initial antigenic priming is given by a gene-based vaccine (in the form of viral vector or DNA plasmid), followed by a boost of matching Ag in the form of recombinant protein, has become a promising strategy to elicit immune protection and high quality antibody responses. Our previous research has established that a prime-boost system with HIV gp120 as the Ag is capable of inducing bnAbs in humans when the antigens were delivered as a polyvalent formulation by the DNA prime-protein boost approach. Typically, bnAbs are the product of extensive B cell clonal selection and evolution, and display a high degree of somatic hypermutation. Thus, inducing bnAbs requires a strong germinal center (GC) reaction. Because the GC reaction is dependent upon specialized follicular helper T cells (TFH cells), we investigated whether prime-boost vaccination affected the development of TFH cells. Our preliminary work revealed that DNA priming followed by protein boosting led to augmented TFH cell development, greatly enhanced GC development, and higher Ab titers and functional affinity, compared to protein immunization alone. However, the detailed immunological mechanisms controlling TFH development and activity in an HIV-1 vaccine setting are completely unknown. We have developed the hypothesis that 1) compared to protein priming, gp120 DNA priming induces a better TFH cell response, 2) careful coordination of priming and boosting immunizations affecting TFH cells and the germinal center response is crucial for the development of anti-gp120-specific antibodies at the end of prime-boost process, and 3) a stronger TFH response correlates with detectable circulating "blood-TFH cells" in both mice and humans. In the current proposal, we will investigate the mechanisms by which DNA priming induces TFH cells, and how this allows the host to produce high-level Ab responses following booster vaccinations. Our ultimate goal is to use this knowledge to foster the development of a highly effective HIV vaccine.

产品说明：预防人类免疫缺陷病毒1型（HIV-1）传播的一个主要目标是开发具有广泛保护性的疫苗。然而，由于HIV-1的极端遗传多样性和HIV-1 Env抗原的免疫原性差，这一目标一直难以实现。有效保护性HIV-1疫苗的一个关键要素是广泛中和抗体（bnAbs），它可以阻止不同类型的主要HIV-1病毒分离株的感染。虽然已经从HIV感染的患者中鉴定出bnAb，但是如何通过疫苗接种诱导bnAb的问题一直存在。最近，异源初免-加强方法，其中通过基于基因的疫苗（以病毒载体或DNA质粒的形式）给予初始抗原初免，随后以重组蛋白的形式加强匹配的Ag，已成为引发免疫保护和高质量抗体应答的有前景的策略。我们以前的研究已经确定，当抗原通过DNA引发-蛋白加强方法作为多价制剂递送时，以HIV gp 120作为Ag的引发-加强系统能够在人体中诱导bnAb。通常，bnAb是广泛的B细胞克隆选择和进化的产物，并显示高度的体细胞超突变。因此，诱导bnAb需要强的生发中心（GC）反应。由于GC反应依赖于特化的滤泡辅助性T细胞（TFH细胞），我们研究了初免-加强疫苗接种是否影响TFH细胞的发育。我们的初步工作表明，与单独的蛋白免疫相比，DNA引发随后蛋白加强导致增强的TFH细胞发育，大大增强的GC发育，以及更高的Ab滴度和功能亲和力。然而，在HIV-1疫苗环境中控制TFH发展和活性的详细免疫学机制是完全未知的。我们已经提出了以下假设：1）与蛋白质引发相比，gp 120 DNA引发诱导更好的TFH细胞应答，2）影响TFH细胞的引发和加强免疫的仔细协调以及生发中心应答对于在引发-加强过程结束时产生抗gp 120特异性抗体至关重要，和3）在小鼠和人中，更强的TFH应答与可检测的循环“血液-TFH细胞”相关。在目前的建议中，我们将研究DNA引发诱导TFH细胞的机制，以及这如何使宿主在加强疫苗接种后产生高水平的抗体应答。我们的最终目标是利用这些知识来促进高效艾滋病毒疫苗的开发。