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型HIV疫苗诱导的免疫反应。研制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相关保护。迄今在功效试验中测试的两种疫苗策略未能产生保护作用。我们实验室开发的疫苗策略侧重于直接利用树突状细胞的潜力，以提高免疫反应的强度和质量，无论是单独还是与其他策略相结合。HIV抗原在融合单克隆抗体中通过DEC-205（一种内噬性树突状细胞受体）直接递送到成熟的树突状细胞。我们已经证明，用含有poly - IC的anti-DEC-205 HIV Gag p24融合单抗作为佐剂，在小鼠中诱导保护性免疫。此外，我们有初步的数据表明，通过DEC-205受体靶向HIV抗原，在来自HIV感染个体的pbmc中，诱导HIV特异性CD4+和CD8+ T细胞回忆反应。我提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反应。所提出的免疫测定法可能对评价未来的HIV候选疫苗有用。我们的研究还将探讨HIV免疫原的最佳选择，以在不损害抗原加工和呈递的情况下实现更广泛的病毒覆盖。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的培训和免疫分析的实验室经验，以及通过课程、研讨会和会议进行广泛的教学。在Steinman博士、Schlesinger博士和Markowitz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，并发展临床和实验室研究技能，长期目标是成为艾滋病毒疫苗转化研究的独立研究人员。

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.