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

描述(由申请人提供)：我的目标是评估一种新的艾滋病毒疫苗诱导的免疫反应。开发有效的艾滋病毒疫苗面临着前所未有的挑战，例如艾滋病毒-1病毒的异常多样性，以及缺乏明确的免疫保护相关性。到目前为止，在功效试验中测试的两种疫苗策略都未能诱导保护。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数量和质量，无论是单独还是与其他策略结合使用。HIV抗原通过融合的单抗通过DEC-205直接传递给成熟的树突状细胞，DEC-205是一种内细胞性树突状细胞受体。结果表明，以抗DEC-205HIV-Gag p24融合单抗为佐剂，免疫小鼠可诱导保护性免疫。此外，我们有初步数据显示，通过DEC-205受体在HIV感染者的PBMC中靶向HIV抗原，可以诱导HIV特异性的CD4+和CD8+T细胞召回反应。我建议进行的研究将调查以DEC为靶标的HIV疫苗在健康志愿者中产生的主要免疫反应。拟议的免疫分析可能会对未来的艾滋病毒候选疫苗的评估有用。我们的研究还将调查艾滋病毒免疫原的最佳选择，以实现更广泛的病毒覆盖，而不损害抗原处理和呈递。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。这项K23应用的教育计划包括进行早期临床试验的培训和免疫学分析的实验室经验，以及通过课程作业、研讨会和会议进行广泛的教学。在斯坦曼博士、施莱辛格博士和马科维茨博士的指导下，在洛克菲勒大学提供的研究环境和支持下，我将能够进行拟议的研究并培养临床和实验室研究技能，长期目标是成为艾滋病毒疫苗翻译研究的独立研究员。 相关性：到目前为止，测试的几种艾滋病毒疫苗未能诱导对感染艾滋病毒的保护。需要新的战略来解决这一全球问题。树突状细胞(DC)是免疫系统中的细胞，识别并向其他类型的免疫细胞递送外来蛋白，导致一系列免疫反应。DEC205 HIV疫苗将HIV蛋白传递给DC，并诱导针对HIV的免疫反应。

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.