Antigen-Specific NK Cell Memory Against SIV and HIV Vaccines

针对 SIV 和 HIV 疫苗的抗原特异性 NK 细胞记忆

基本信息

批准号：
9405715
负责人：
Roger Keith Reeves
金额：
$ 87.66万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-25 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9405715
关键词：
Address Adenoviruses Animals Antigens Cells Chronic Clone Cells Cloning Containment Coupled Cytolysis Cytomegalovirus Data Dendritic Cells Development Disease Disease Progression Distal Exhibits GAG Gene Genetic Transcription Grant HIV HIV Infections HIV vaccine HIV-1 Hepatic Human Immune response Infection Innate Immune Response Kinetics Longevity Macaca Macaca mulatta Maintenance Measures Mediating Memory Molecular Mus Natural Immunity Natural Killer Cells Outcome Pathway interactions Patients Peptides Phenotype Physiologic pulse Play Primates Property Proteins Recombinants Role SIV Sampling Series Shapes Site Specificity Structure Techniques Testing Time Tissues Vaccinated Vaccination Vaccine Antigen Vaccine Research Vaccines Viral Antigens Virus Virus Diseases Work antigen processing arm base cell killing cytotoxicity experimental study field study memory recall mouse model natural killer cell protein 44-kDa neoplastic cell pathogen peripheral blood receptor function response simian human immunodeficiency virus trafficking transcriptome sequencing vector vector vaccine

项目摘要

Natural killer (NK) cells provide rapid early responses to viral infections and thus can contribute substantially to disease modulation and vaccine protection. Traditionally, NK cells have been considered to be nonspecific components of innate immunity, but recent studies in mice have shown that NK cells can also demonstrate features of antigen-specific memory. Until recently it was unclear whether this phenomenon might exist in primates, but our preliminary data demonstrates for the first time evidence of antigen-specific NK cell memory in any primate species. As compared with NK cells from uninfected macaques, splenic and hepatic NK cells from simian immunodeficiency virus (SIV)-infected animals were highly reactive to Gag- and Env-pulsed dendritic cells (DCs) but not to mock-pulsed DCs or mis-matched antigen controls. Similar Gag-specific NK cell responses were found in treated and untreated HIV-1- infected patients. Interestingly, memory NK cell responses in peripheral blood were low compared to distal sites, suggesting memory NK cells reside predominantly in tissues. We also found NK cell memory responses in rhesus macaques for over 5 years following vaccination with recombinant Ad26 vectors expressing HIV-1 Env or SIV Gag indicating antigen-specific NK cell memory is durable and does not require ongoing antigenic stimulation. The longevity, functionality, and specificity of memory NK cell responses in primates suggest their functional relevance and their potential importance against HIV-1 and other pathogens. In this new proposal we will address major deficits to this new field of study including identifying the mechanisms, kinetics, distribution, and efficacy of these responses using state-of-the-art techniques. We will evaluate the overarching hypothesis that memory NK cell responses elicited against SIV/HIV and adenovirus vaccine vectors are long-lived even in the absence of replicating virus and can be mobilized to engage and lyse virus-infected cells in an antigen- specific manner. We will evaluate this hypothesis with three focused Specific Aims: (1) Evaluate mobilization and recall of memory NK cells elicited against HIV and SIV vaccine antigens in humans and macaques; (2) Evaluate mobilization and maintenance of memory NK cells after SIV challenge in vaccinated and unvaccinated macaques; and (3) Explore cellular and molecular mechanisms of memory NK cell recognition and specificity.

自然杀伤 (NK) 细胞对病毒感染提供快速的早期反应，从而有助于对疾病调节和疫苗保护具有重大意义。传统上，NK 细胞被认为是先天免疫的非特异性成分，但最近对小鼠的研究发现表明 NK 细胞还可以表现出抗原特异性记忆的特征。直到最近它目前尚不清楚这种现象是否存在于灵长类动物中，但我们的初步数据首次证明任何抗原特异性 NK 细胞记忆的证据灵长类物种。与来自未感染猕猴的 NK 细胞相比，脾脏和肝脏的 NK 细胞来自猿猴免疫缺陷病毒 (SIV) 感染动物的 NK 细胞对 Gag 和 Env 脉冲的树突状细胞 (DC)，但不适用于模拟脉冲的 DC 或不匹配的抗原控制。在治疗和未治疗的 HIV-1- 中发现了类似的 Gag 特异性 NK 细胞反应感染的患者。有趣的是，外周血中的记忆 NK 细胞反应较低与远端部位相比，表明记忆 NK 细胞主要存在于组织中。我们也发现恒河猴在接种疫苗后 5 年多内仍能保持 NK 细胞记忆反应重组Ad26载体表达HIV-1 Env或SIV Gag，表明抗原特异性 NK 细胞记忆持久，不需要持续的抗原刺激。这灵长类动物记忆 NK 细胞反应的寿命、功能性和特异性表明它们的功能相关性及其针对 HIV-1 和其他病原体的潜在重要性。在这个新提案我们将解决这一新研究领域的主要缺陷，包括确定使用最先进的技术研究这些反应的机制、动力学、分布和功效技术。我们将评估记忆 NK 细胞反应的总体假设即使在没有病毒的情况下，针对 SIV/HIV 和腺病毒疫苗载体的寿命也很长复制病毒，并且可以动员起来以抗原形式接合并裂解病毒感染的细胞具体方式。我们将通过三个重点具体目标来评估这一假设：(1) 评估针对 HIV 和 SIV 疫苗抗原引发的记忆 NK 细胞的动员和回忆在人类和猕猴中； (2) 评估记忆NK的动员和维持接种疫苗和未接种疫苗的猕猴中 SIV 攻击后的细胞； (3) 探索记忆 NK 细胞识别和特异性的细胞和分子机制。