HIV vaccination via inhibition of cytokine signaling inhibitors

描述（由申请人提供）：尽管进行了广泛的努力，没有或很少有希望的HIV候选疫苗已经出现。由于对HIV的天然免疫应答是无效的，因此可能需要产生上级天然抗HIV免疫应答的免疫应答。因此，迫切需要探索替代免疫方法。抗原呈递细胞（APC）在启动和维持抗HIV感染的免疫应答中起关键作用，并且受刺激性和抑制性信号的调节。细胞因子信号转导抑制因子1（SOCS 1）通过阻断APCs中的JAK-STAT信号通路在免疫应答中起关键的抑制作用。我们最近的研究表明，DC的刺激能力和获得性免疫的大小是由DC中的SOCS 1关键控制的，并且SOCS 1沉默的DC诱导增强的CTL和针对HIV抗原的抗体应答。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siSOCS 1和修饰的HIV免疫原的慢病毒载体进行体内疫苗接种使转导的APC中的JAK/STAT信号传导抑制剂SOCS 1沉默，从而增强其免疫刺激效力，延长其存活，并赋予其持续刺激HIV特异性细胞和体液应答的能力。本研究的具体目的是：1）测试用共表达抑制JAK/STAT信号传导的关键抑制剂的SiSOCS 1和修饰的HIV免疫原的慢病毒载体进行体内免疫增强HIV疫苗诱导HIV特异性CD 8+和CD 4 + T细胞和抗体应答的能力的假设。2)为了检验促炎细胞因子和其信号传导抑制剂的抑制剂（siSOCS 1）的共表达更有效地诱导记忆HIV特异性CD 8+和CD 4 + T细胞和抗体应答的假设。3)为了验证通过体内慢病毒免疫转导的SOCS 1沉默的抗原呈递细胞可以持续激活HIV特异性细胞和体液应答的假设。据我们所知，本研究中提出的这种疫苗接种策略代表了通过抑制宿主的信号传导抑制剂来增强抗HIV免疫力的第一个例子。这种SOCS 1沉默方法可以普遍适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HIV候选疫苗，可以在非人灵长类动物中进一步评估，并最终在人类中进行评估。

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.