New adjuvants to induce neutralizing HIV antibody responses

诱导中和艾滋病毒抗体反应的新佐剂

基本信息

批准号：
8921780
负责人：
Si-Yi Chen
金额：
$ 24.75万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8921780
关键词：
Adjuvant Antibodies Antibody Response Antigen-Presenting Cells Antigens Autoantigens B-Cell Activation B-Lymphocytes Binding CISH gene Cell physiology Cyclic GMP DNA Dendritic Cells Dendritic cell activation Development Epitopes Feedback Genetic Transcription HIV HIV Antibodies HIV Infections HIV vaccine Humoral Immunities Immune Immune response Immune system Immunization In Vitro Infection Inflammatory Interferon Type I Lead Ligands Membrane Molecular Monitor Mus Nucleotides Pathway interactions Pattern recognition receptor Pilot Projects Play Regulation Role Second Messenger Systems Self Tolerance Signal Pathway Signal Transduction Stimulus Structure Testing Toll-like receptors Vaccination Viral base cytokine ds-DNA extracellular immune activation in vivo inhibitor/antagonist insight microbial mimicry neutralizing antibody novel programs public health relevance receptor response second messenger vaccine development

项目摘要

DESCRIPTION (provided by applicant): Natural immune responses and vaccination are unable to induce protective antibody responses against HIV infection. Despite the presence of neutralizing epitopes, such as the membrane-proximal external region (MPER), on HIV envelope (Env), Env immunization has so far failed to elicit such neutralizing antibodies. A body of evidence suggests that an immunological tolerance mechanism may contribute to the loss or poor activation of MPER-reactive B cells due to a structural mimicry with self-antigens. Dendritic cells (DCs) use pattern-recognition receptors to monitor conserved microbial structures at extracellular, endosomal, and intracellular compartments for signs of infection for triggering immune activation. In response to cytosolic DNA, the immune system mounts a programed response that involves the transcription of type I interferons and inflammatory cytokines. Cytosolic DNA was recently found to induce the synthesis of cyclic GMP-AMP (cGAMP) di-nucleotide upon binding to cGAMP synthase (cGAS). cGAMP subsequently activates proinflammatory responses by binding to a downstream receptor STING. Hence, the recent discovery of the cGAS-cGAMP second messenger pathway provides critical insights into the molecular basis of immune activation, as well as uncovers new avenues to develop adjuvants. Moreover, DC functions are critically regulated by immune stimuli, as well as inhibitors. Our studies demonstrate that the immunostimulatory ability of DCs is critically suppressed by SOCS1, a feedback inhibitor of the JAK/STAT signal pathway, and that SOCS1-silenced DCs are hyperactivated and can effectively induce antigen-specific antibody responses. In this study, we aim to explore the adjuvant potential of cGAMP, the second messenger of cytosolic dsDNA sensing, in combination with SOCS1 antagonist for activating anti-HIV antibody responses. The hypothesis of this study is that the combined use of cGAMP and SOCS1 antagonist will endow DCs with superior immunostimulatory potency to break self tolerance and to induce anti-HIV antibody responses against the conservative, neutralizing MPER epitope. The specific aims of this study are: Aim 1. To test whether cGAMP has an immunostimulatory effect on DCs, leading to the activation of B cells and anti-HIV Env antibody responses. Aim 2. To test whether cGAMP and SOCS1 antagonist have a synergistic, stimulatory effect on DCs by activating STING and inhibiting SOCS1 to break self-tolerance and to activate stronger anti-HIV antibody responses against the conservative, neutralizing MPER epitope. This study may lead to the development of cGAMP and the combined use of cGAMP and SOCS1 antagonist as novel adjuvants for HIV vaccine development.

描述（由申请人提供）：尽管 HIV 包膜 (Env)、Env 上存在中和表位，例如近膜外部区域 (MPER)，但自然免疫反应和疫苗接种无法诱导针对 HIV 感染的保护性抗体反应。迄今为止，免疫接种未能引发此类中和抗体，大量证据表明，由于与自身抗原的结构拟态，免疫耐受机制可能导致 MPER 反应性 B 细胞的丧失或活化不良。树突状细胞 (DC) 使用模式识别受体来监测细胞外、内体和细胞内区室的保守微生物结构，以寻找触发免疫激活的感染迹象。最近发现 I 型干扰素和炎症细胞因子在与 cGAMP 合酶结合后诱导环 GMP-AMP (cGAMP) 二核苷酸的合成。 (cGAS) 随后通过与下游受体 STING 结合来激活促炎反应，因此，最近发现的 cGAS-cGAMP 第二信使途径为免疫激活的分子基础提供了重要的见解，并揭示了开发佐剂的新途径。此外，DC 功能受到免疫刺激和抑制剂的严格调节，我们的研究表明，SOCS1（JAK/STAT 信号的反馈抑制剂）严重抑制 DC 的免疫刺激能力。在本研究中，我们旨在探索胞质 dsDNA 传感的第二信使 cGAMP 与 SOCS1 拮抗剂联合使用以激活抗抗原特异性抗体反应。 -HIV抗体反应。本研究的假设是cGAMP和SOCS1拮抗剂的联合使用将赋予DCs优异的免疫刺激效力，以打破自我耐受并诱导抗HIV抗体反应。本研究的具体目的是：目的 1. 测试 cGAMP 是否对 DC 具有免疫刺激作用，从而激活 B 细胞和抗 HIV Env 抗体反应。 cGAMP 和 SOCS1 拮抗剂是否对 DC 具有协同刺激作用，通过激活 STING 并抑制 SOCS1 来打破自我耐受并激活更强的抗 HIV 抗体反应这项研究可能会导致 cGAMP 的开发以及 cGAMP 和 SOCS1 拮抗剂联合使用作为 HIV 疫苗开发的新型佐剂。