Characterization of the immunity induced by a DEC205-targeted HIV vaccine

描述（由申请人提供）：我的目标是评价一种新型HIV疫苗诱导的免疫应答。开发有效的HIV疫苗面临着前所未有的挑战，例如HIV-1病毒的非凡多样性以及缺乏明确的免疫保护相关性。迄今为止，在功效试验中测试的两种疫苗策略未能诱导保护。我们实验室开发的疫苗策略专注于直接利用树突状细胞的潜力来提高免疫反应的强度和质量，无论是单独使用还是与其他策略相结合。HIV抗原在融合单克隆抗体内通过DEC-205（一种内吞树突状细胞受体）直接递送至成熟树突状细胞。我们已经证明，用抗DEC-205 HIV Gag p24融合mAb与聚IC作为佐剂进行初免-加强免疫，在小鼠中诱导保护性免疫。此外，我们有初步数据显示，通过DEC-205受体靶向HIV抗原，在HIV感染个体的PBMC中，诱导HIV特异性CD 4+和CD 8 + T细胞回忆应答。我建议进行的研究将调查DEC靶向HIV疫苗在健康志愿者中产生的初级免疫应答。建议的免疫测定可能被证明是有用的，为未来的HIV疫苗候选人的评价。我们的研究还将调查HIV免疫原的最佳选择，以实现更广泛的病毒覆盖，而不损害抗原加工和呈递。如果成功，我们的疫苗方法将增加目前的艾滋病毒疫苗战略库。该K23应用程序的教育计划包括进行早期临床试验和免疫测定实验室经验的培训，沿着通过课程、研讨会和会议进行的广泛的教学。在Steinman博士，Schlesinger博士和Markowitz博士的指导下，并在洛克菲勒大学提供的研究环境和支持下，我将能够执行拟议的研究并发展临床和实验室研究技能，长期目标是成为HIV疫苗转化研究的独立研究员。 相关性：迄今为止测试的几种艾滋病毒疫苗未能诱导预防艾滋病毒感染。需要新的战略来解决这一全球性问题。树突状细胞（DC）是免疫系统的细胞，其识别并将外源蛋白呈递给其他免疫细胞类型，导致免疫应答级联。DEC 205 HIV疫苗将HIV蛋白递送至DC并诱导针对HIV的免疫应答。

DESCRIPTION (provided by applicant): My goal is to evaluate the immune responses induced by a novel HIV vaccine. There are unprecedented challenges to the development of an effective HIV vaccine, such as the extraordinary viral diversity of HIV-1 and the lack of clear immune correlates of protection. Two vaccine strategies tested in efficacy trials to date have failed to induce protection. The vaccine strategy developed in our laboratory focuses on directly exploiting dendritic cells' potential to improve the magnitude and quality of immune responses, either alone or in combination with other strategies. HIV antigens are delivered within fusion monoclonal antibodies directly to maturing dendritic cells via DEC-205, an endocytic dendritic cell receptor. We have shown that prime-boost immunization with anti-DEC-205 HIV Gag p24 fusion mAb with poly IC, as an adjuvant, induces protective immunity in mice. In addition, we have preliminary data showing that targeting of HIV antigens via DEC-205 receptor, in PBMCs from HIV-infeced individuals, induces both HIV-specific CD4+ and CD8+ T cell recall responses. The studies I propose to perform will investigate the primary immune responses generated by DEC-targeted HIV vaccines in healthy volunteers. The proposed immuno assays may prove useful for the evaluation of future HIV vaccine candidates. Our studies will also investigate optimal choices of HIV immunogens to achieve broader viral coverage without compromise of antigen processing and presentation. If successful, our vaccine approach will add to the current arsenal of HIV vaccine strategies. The educational plan of this K23 application includes training in the conduct of early phase clinical trials and laboratory experience in immunological assays along with extensive didactic teaching through coursework, seminars and conferences. Under the guidance of Dr. Steinman, Dr. Schlesinger and Dr. Markowitz, and with the research environment and support provided at the Rockefeller University, I will be able to perform the proposed sutdies and develop both clinical and laboratory research skills with the long term goal of becoming an independet researcher in HIV vaccine translational research. RELEVANCE: Several HIV vaccines tested to date failed to induce protection against acquisition of HIV infection. New strategies are needed to address this global problem. Dendritic cells (DCs) are cells of the immune system that recognize and present foreign proteins to other immune cell types leading to a cascade of immune responses. DEC205 HIV vaccine delivers HIV proteins to DCs and induces immune responses against HIV.