New adjuvants to induce neutralizing HIV antibody responses

诱导中和艾滋病毒抗体反应的新佐剂

• 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
• 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

 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（由应用提供）：天然免疫复杂和疫苗接种无法诱导针对HIV感染的保护抗体反应。尽管存在中和表位，例如在HIV包膜上（ENV）上的膜 - 斑点外部区域（MPER），但到目前为止，ENV免疫启动未能引起这种中和的抗体。大量证据表明，由于具有自我抗原的结构模仿，一种免疫耐受性机制可能导致MPER反应性B细胞的丧失或不良激活。树突状细胞（DCS）使用模式识别受体来监测细胞外，内体和细胞内隔室在感染的迹象上，以触发免疫激活。为了响应胞质DNA，免疫系统安装了涉及I型干扰素和炎性细胞因子的转录的编程反应。最近发现胞质DNA在与CGAMP合酶（CGAS）结合后诱导环状GMP-AMP（CGAMP）二核苷酸的合成。 CGAMP随后通过与下游接收器的刺激结合来激活促炎反应。因此，最近发现CGAS-CGAMP第二信使途径为免疫激活的分子基础提供了关键的见解，并发现了开发调节器的新途径。此外，直流功能受到免疫刺激以及抑制剂的严格调节。我们的研究表明，DC的免疫刺激能力受到SOCS1的严重抑制，SOCS1是JAK/STAT信号途径的反馈抑制剂，并且SOCS1中脱毛的DC被过度激活，并且可以有效诱导抗原特异性抗体反应。在这项研究中，我们旨在探索CGAMP的可调节电位，CGAMP是胞质DSDNA传感的第二个使者，并结合SOCS1拮抗剂来激活抗HIV抗体反应。这项研究的假设是，CGAMP和SOCS1拮抗剂的联合使用将赋予DC具有优异的免疫刺激效力，以破坏自耐受性并诱导对保守派的抗HIV抗体反应，从而对MPER中和MPER表现。这项研究的具体目的是：目标1。测试CGAMP是否对DC具有免疫刺激作用，从而导致B细胞激活和抗HIV ENV抗体反应。目的2。通过激活刺痛并抑制SOCS1破坏自耐受性并激活对保守的抗HIV抗体反应，对DC具有协同的刺激作用，对DC具有协同的刺激作用，以对DC具有协同的刺激作用。这项研究可能导致CGAMP的发展以及CGAMP和SOCS1拮抗剂作为HIV疫苗发育的新型调节器的综合使用。