New adjuvants to induce neutralizing HIV antibody responses

 描述（由申请方提供）：自然免疫应答和疫苗接种不能诱导针对HIV感染的保护性抗体应答。尽管在HIV包膜（Env）上存在中和表位，例如膜近端外部区域（MPER），但Env免疫迄今未能引发这样的中和抗体。大量证据表明，由于自身抗原的结构模拟，免疫耐受机制可能导致MPR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，以发现感染的迹象，从而触发免疫激活。免疫系统对胞质DNA的应答包括I型干扰素和炎性细胞因子的转录。最近发现细胞溶质DNA在与环GMP-AMP（cGAMP）合酶（cGAS）结合时诱导环GMP-AMP（cGAMP）二核苷酸的合成。cGAMP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第二信使途径提供了关键的见解免疫激活的分子基础，以及发现新的途径，开发佐剂。此外，DC功能受到免疫刺激物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JAK/STAT信号通路的反馈抑制剂SOCS 1的严重抑制，并且SOCS 1沉默的DC被过度激活，并且可以有效地诱导抗原特异性抗体应答。在这项研究中，我们的目的是探索cGAMP，胞质dsDNA传感的第二信使，结合SOCS 1拮抗剂激活抗HIV抗体反应的佐剂潜力。本研究的假设是，cGAMP和SOCS 1拮抗剂的联合使用将赋予DC上级免疫刺激效力，以打破自身耐受并诱导针对保守的中和MPER表位的抗HIV抗体应答。本研究的具体目标是：目标1。测试cGAMP是否对DC具有免疫刺激作用，从而导致B细胞的活化和抗HIV Env抗体应答。目标2.测试cGAMP和SOCS 1拮抗剂是否通过激活STING和抑制SOCS 1对DC具有协同刺激作用，以打破自身耐受性并激活针对保守中和MPER表位的更强抗HIV抗体应答。这项研究可能会导致cGAMP的发展和cGAMP和SOCS 1拮抗剂的联合使用作为艾滋病毒疫苗开发的新佐剂。

 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.