Use of a Novel Antigen Loading Platform for Dendritic Cell-Based HIV Vaccines

描述（由申请人提供）：产生人CD 4+和CD 8 + T细胞应答的有效方法是通过在树突状细胞（DC）上呈递抗原，树突状细胞是刺激先天性和适应性免疫应答的抗原呈递细胞（APC）系统。利用或靶向人DC以增强慢性HIV感染中的免疫力的免疫策略在先前的研究中显示出希望，但需要进一步的研究来优化DC疫苗候选物。理想情况下，DC靶向疫苗载体应递送相关HIV抗原用于呈递，同时激活DC以上调表面共刺激分子并产生pro Th 1细胞因子，以引发HIV特异性多功能CD 4+和CD 8 + T细胞应答。重组灭活但具有代谢活性的单核细胞增生李斯特菌载体可以满足这些标准，同时与各种减毒病毒和细菌载体相比，在免疫原性和安全性方面提供潜在优势。在拟议的研究中，将使用重组灭活但代谢活性的表达HIV-1 gag的单核细胞增生李斯特菌（KBMA Lm-gag）作为DC的抗原加载和活化/成熟平台，以评估其在DC疫苗制剂中用于慢性HIV感染的潜在用途。具体目标是：（2）评估KBMA Lm-gag感染的源自HIV血清阳性患者的DC引发初始T细胞以形成具有高功能亲合力的多功能HIV-1 gag特异性CD 4+和CD 8 + T细胞的能力;和（3）研究预先存在的对Lm的免疫是否影响由KBMA lm-gag感染的DC在免疫原性、免疫活化和CD 4 + T细胞对HIV感染的易感性方面引起的应答。这些研究将有助于确定KBMA Lm-gag是否可以作为一种令人兴奋的新载体，用于利用或靶向DC以促进控制HIV感染的HIV免疫治疗。相关性（参见说明）：HIV疫苗学领域最近遭受挫折，激发了对抗原递送新模式的研究，以刺激HIV特异性免疫。为了从这一点上向前迈进，我们已经应用了从失败尝试中获得的知识的各个方面来设计和评价拟议研究中使用的结构。

DESCRIPTION (provided by applicant): An effective way to generate human CD4+ and CD8+ T cell responses is by presenting antigens on dendritic dells (DCs), a system of antigen presenting cells (APCs) that stimulate innate and adaptive immune responses. Immunization strategies that utilize or target human DCs to enhance immunity in chronic HIV infection have shown promise in previous studies, but further research is required to optimize DC vaccine candidates. Ideally, a DC-targeting vaccine vector should deliver relevant HIV antigens for presentation, while concurrently activating DCs to upregulate surface costimulatory molecules and produce pro Th1 cytokines in order to prime HIV-specific polyfunctional CD4+ and CD8+ T cell responses. Recombinant killed but metabolically active Listeria Monocytogenes vectors may fulfill these criteria, while offering potential advantages in terms of both immunogenicity and safety when compared with various attenuated viral and bacterial vectors. In the proposed research, the use of a recombinant killed but metabolically active Listeria Monocytogenes expressing HIV-1 gag (KBMA Lm-gag) will be investigated as an antigen loading and activation/maturation platform for DCs to evaluate its potential use in DC vaccine formulations for chronic HIV infection. The specific aims are to: (1) assess activation/maturation and efficiency of antigen presentation of DCs derived from HIV seropositive donors following infection with KBMA Lm-gag; (2) evaluate the ability of KBMA Lm-gag infected DCs derived from HIV seropositive patients to prime naive T cells to form polyfunctional HIV-1 gag-specific CD4+ and CD8+ T cells that possess high functional avidity; and (3) investigate whether pre-existing immunity to Lm impacts responses elicited by KBMA lm-gag infected DCs in terms of immunogenicity, immune activation, and susceptibility of CD4+ T cells to HIV infection. These studies will help determine whether KBMA Lm-gag may serve as an exciting new vector for HIV immunotherapy that utilizes or targets DCs to facilitate control of HIV infection. RELEVANCE (See instructions): The field of HIV vaccinology has recently suffered set-backs, inspiring the investigation of novel modes of antigen delivery in order to stimulate HIV-specific immunity. In order to move forward from this point, we have applied aspects of the knowledge gained from failed attempts to the design and evaluation of the construct utilized in the proposed study.