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，但没有或几乎没有出现有前途的艾滋病毒候选疫苗。由于对艾滋病毒的自然免疫反应是无效的，因此可能需要产生优于自然抗艾滋病毒免疫反应的免疫反应。因此，迫切需要探索替代免疫方法。抗原提呈细胞(APC)在启动和维持针对HIV感染的免疫反应中起着关键作用，并受刺激和抑制信号的调节。细胞因子信号转导抑制因子1(SOCS1)通过阻断APC的JAK-STAT信号通路，在免疫反应中发挥关键的抑制作用。我们最近的研究表明，树突状细胞的刺激能力和获得性免疫的大小是由树突状细胞中的SOCS1关键控制的，并且SOCS1沉默的树突状细胞诱导针对HIV抗原的CTL和抗体应答增强。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物来预防或控制HIV感染。本研究的中心假设是，共表达siSOCS1的慢病毒载体和修饰的HIV免疫原在体内接种后，可以沉默转导的APC中的JAK/STAT信号抑制物SOCS1，从而增强它们的免疫刺激效力，延长它们的存活时间，并赋予它们持续刺激HIV特异性细胞和体液反应的能力。本研究的具体目的是：1)验证共表达抑制JAK/STAT信号的关键抑制因子SiSOCS1的慢病毒载体和修饰的HIV免疫原体内免疫增强HIV疫苗诱导HIV特异性CD8+和CD4+T细胞和抗体应答的能力的假设。2)验证促炎细胞因子及其信号抑制因子抑制物(SiSOCS1)共表达能更有效地诱导记忆HIV特异性CD8+和CD4+T细胞和抗体反应的假说。3)验证慢病毒体内免疫转导的SOCS1沉默的抗原提呈细胞能够持续激活HIV特异性细胞和体液反应的假说。据我们所知，这项研究中提出的疫苗接种策略是通过抑制宿主的信号抑制物来增强抗HIV免疫的第一个例子。这种SOCS1沉默方法可普遍适用于提高各种形式的艾滋病毒疫苗的效力。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身上进一步评估，最终在人类身上进行评估。

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.