HIV vaccination via inhibition of cytokine signaling inhibitors

通过抑制细胞因子信号抑制剂进行艾滋病毒疫苗接种

• 批准号: 7408072
• 负责人: Si-Yi Chen
• 金额: $ 34.93万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408072
• 关键词: Adjuvant; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptotic; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Cytokine Inducible SH2-Containing Protein; Cytokine Signaling; Dendritic Cells; Goals; HIV; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; Human; Immune; Immune response; Immunity; Immunization; Infection; Knowledge; Lentivirus Vector; Maintenance; Memory; Monkeys; Mus; Natural Immunity; Numbers; Play; Principal Investigator; Role; Signal Pathway; Signal Transduction; System; Testing; Vaccination; Vaccines; cytokine; in vivo; inhibitor/antagonist; lymph nodes; nonhuman primate; prevent; programs; response; vaccination strategy

DESCRIPTION (provided by applicant): Despite extensive efforts, no or few promising HIV vaccine candidate has emerged. Since the natural immune response to HIV is ineffective, it may be necessary to generate immune responses that are superior to the natural anti-HIV immune responses. Thus, there is an urgent need to explore alternative immunization approaches. Antigen-presenting cells (APCs) play a critical role in the initiation and maintenance of immune response against HIV infection, and are regulated by stimulatory as well as inhibitory signaling. The suppressor of cytokine signaling 1 (SOCS1) plays a critical inhibitory role in immune responses by blocking the JAK-STAT signaling pathway in APCs. Our recent studies demonstrate that the stimulatory capacity of DCs and the magnitude of adaptive immunity are critically controlled by SOCS1 in DCs, and SOCS1-silenced DCs induce an enhanced CTL and antibody response against HIV antigens. The goal of this study is to develop an effective vaccination strategy to prevent or control HIV infection by the inhibition of cytokine signaling inhibitors in APCs. The central hypothesis of this study is that in vivo vaccination with lentiviral vectors coexpressing siSOCSl and a modified HIV immunogen silences the JAK/STAT signaling inhibitor SOCS1 in transduced APCs, thus enhancing their immunostimulatory potency, prolonging their survival, and endowing them with the ability to persistently stimulate HIV-specific cellular and humoral responses. The specific aims of this study are: 1) To test the hypothesis that in vivo immunization with lentiviral vectors coexpressing SiSOCSl, which inhibits the key inhibitor of JAK/STAT signaling, and a modified HIV immunogen enhances the ability of HIV vaccine to induce both HIV-specific CD8+ and CD4+ T cell and antibody responses. 2) To test the hypothesis that coexpression of a proinflammatory cytokine and the inhibitor of its signaling inhibitor (siSOCSl) more efficiently induces memory HIV-specific CD8+ and CD4+ T cell and antibody responses. 3) To test the hypothesis that SOCS1-silenced antigen-presenting cells transduced by in vivo lentiviral immunization can persistently activate HIV-specific cellular and humoral responses. This vaccination strategy proposed in this study, to our knowledge, represents the first example of enhancing anti-HIV immunity by inhibiting a host's signaling inhibitor. This SOCS1 silencing approach could be generally applicable to enhancing the potency of various forms of HIV vaccines. Importantly, this study aims to develop a HIV vaccine candidate, which could be further evaluated in non-human primates and ultimately in humans.

描述（由申请人提供）：尽管进行了广泛的努力，但没有或很少出现有希望的艾滋病毒候选疫苗。由于针对 HIV 的自然免疫反应无效，因此可能有必要产生优于自然抗 HIV 免疫反应的免疫反应。因此，迫切需要探索替代的免疫方法。抗原呈递细胞 (APC) 在针对 HIV 感染的免疫反应的启动和维持中发挥着关键作用，并受到刺激性和抑制性信号传导的调节。细胞因子信号传导抑制因子 1 (SOCS1) 通过阻断 APC 中的 JAK-STAT 信号传导途径，在免疫反应中发挥关键的抑制作用。我们最近的研究表明，DC 的刺激能力和适应性免疫的强度受到 DC 中 SOCS1 的严格控制，SOCS1 沉默的 DC 会诱导增强的 CTL 和针对 HIV 抗原的抗体反应。本研究的目的是开发一种有效的疫苗接种策略，通过抑制 APC 中的细胞因子信号抑制剂来预防或控制 HIV 感染。本研究的中心假设是，用共表达siSOCS1和修饰的HIV免疫原的慢病毒载体进行体内疫苗接种可沉默转导的APC中的JAK/STAT信号传导抑制剂SOCS1，从而增强其免疫刺激效力，延长其存活时间，并赋予其以下能力：持续刺激 HIV 特异性细胞和体液反应。本研究的具体目的是：1) 检验以下假设：用共表达 SiSOCS1 的慢病毒载体（抑制 JAK/STAT 信号传导的关键抑制剂）和修饰的 HIV 免疫原进行体内免疫可增强 HIV 疫苗诱导 HIV 的能力。 -特异性CD8+和CD4+T细胞和抗体反应。 2)测试以下假设：促炎细胞因子及其信号传导抑制剂的抑制剂(siSOCS1)的共表达更有效地诱导记忆性HIV特异性CD8+和CD4+T细胞和抗体应答。 3) 检验体内慢病毒免疫转导的 SOCS1 沉默抗原呈递细胞可以持续激活 HIV 特异性细胞和体液反应的假设。据我们所知，本研究中提出的疫苗接种策略代表了通过抑制宿主信号抑制剂来增强抗 HIV 免疫力的第一个例子。这种 SOCS1 沉默方法通常可用于增强各种形式的 HIV 疫苗的效力。重要的是，这项研究旨在开发一种艾滋病毒候选疫苗，可以在非人类灵长类动物和最终人类中进行进一步评估。