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

新型抗原装载平台在基于树突状细胞的 HIV 疫苗中的应用

• 批准号: 7922726
• 负责人: Elizabeth Anne Miller
• 金额: $ 13.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922726
• 关键词: Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Attenuated; Avidity; Award; Back; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic; Dendritic Cells; Drug Formulations; Evaluation; Gagging; HIV; HIV Antigens; HIV Infections; HIV vaccine; HIV-1; Human; Immune response; Immunity; Immunization; Immunotherapy; Individual; Infection; Instruction; Investigation; Knowledge; Listeria monocytogenes; Measures; Patients; Phenotype; Predisposition; Recombinants; Research; Research Personnel; Safety; Surface; System; T cell response; T-Lymphocyte; Training; Up-Regulation; Vaccines; Viral; bacterial vector; base; cytokine; design; exhaust; gag Gene Products; ilium; immune activation; immunogenicity; killings; novel; response; skills; vaccine candidate; vaccinology; vector; vector vaccine

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.

描述（由申请人提供）：生成人CD4+和CD8+ T细胞反应的一种有效方法是在树突状销售（DCS）上呈现抗原，这是一种抗原呈递细胞（APC）的系统，刺激先天性和自适应免疫反应。利用或靶向人类DC来增强慢性艾滋病毒感染免疫力的免疫策略在先前的研究中表现出了希望，但是需要进一步的研究来优化DC疫苗候选者。理想情况下，DC靶向疫苗载体应提供相关的HIV抗原以进行呈递，同时激活DC以上调表面刺激性分子并产生Pro Th1细胞因子，以便为HIV特异性的多功能CD4+和CD8+ T细胞反应。与各种衰减病毒和细菌载体相比，重组杀死但代谢活性的单核细胞增生媒介可能会符合这些标准，同时在免疫原性和安全性方面具有潜在的优势。在拟议的研究中，将研究一种表达HIV-1 GAG（KBMA LM-GAG）的重组但代谢活性的单核细胞增生液（KBMA LM-GAG），作为DCS的抗原载荷和激活/成熟平台，用于评估其在慢性HIV感染中的潜在用途。具体目的是：（1）评估用KBMA LM-GAG感染后，来自HIV血清阳性供体的DC的激活/成熟和效率； （2）评估源自HIV血清阳性患者的KBMA LM-GAG感染DC的能力，使其天真T细胞形成多功能HIV-1 GAG特异性CD4+和CD8+ T细胞，具有高功能性感。 （3）调查是否对LM的免疫力是否会影响KBMA LM-GAG感染DC的反应，而DC则是针对免疫原性，免疫激活和CD4+ T细胞对HIV感染的敏感性的影响。这些研究将有助于确定KBMA LM-GAG是否可以作为HIV免疫疗法的令人兴奋的新向量，该疗法利用或靶向DC促进HIV感染的控制。相关性（请参阅说明）：HIV疫苗学领域最近遭受了固定的支持，激发了对新型抗原递送模式的研究，以刺激HIV特异性的免疫力。为了从这一点前进，我们已经应用了从失败的尝试中获得的知识的方面，以设计和评估拟议的研究中使用的结构。