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.

天然杀手（NK）细胞对病毒感染提供了快速的早期反应，因此可以贡献基本上是针对疾病调节和疫苗保护。传统上，NK细胞一直是被认为是先天免疫的非特异性组成部分，但最近在小鼠中的研究表明NK细胞还可以证明抗原特异性内存的特征。直到最近尚不清楚这种现象是否可能存在于灵长类动物中，但是我们的初步数据首次证明任何抗原特异性NK细胞记忆中的证据灵长类动物。与未感染的猕猴，脾和肝的NK细胞相比来自猿猴免疫缺陷病毒（SIV）感染动物的NK细胞高度反应 GAG和环境脉冲的树突状细胞（DC），但不要模拟脉冲或匹配的抗原控件。在处理过的和未处理的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，周围血液中的记忆NK细胞反应较低与远端位点相比，表明记忆NK细胞主要存在于组织中。我们也是在疫苗接种后发现了5年以上的恒河猕猴中的NK细胞记忆反应用表达HIV-1 Env或SIV GAG的重组AD26向量表示抗原特异性 NK细胞存储器耐用，不需要持续的抗原刺激。这灵长类动物中记忆NK细胞反应的寿命，功能和特异性表明他们功能相关性及其对HIV-1和其他病原体的潜在重要性。在这个新建议我们将解决这一新研究领域的主要赤字，包括确定这些反应的机制，动力学，分布和功效技术。我们将评估记忆NK细胞响应的总体假设针对SIV/HIV和腺病毒疫苗载体引起的媒介也长期存在复制病毒，可以动员以参与和裂解感染病毒的细胞具体方式。我们将以三个重点的特定目的评估这一假设：（1）评估对HIV和SIV疫苗抗原引起的记忆NK细胞的动员和回忆在人类和猕猴中；（2）评估记忆NK的动员和维护 SIV挑战后的细胞在接种疫苗和未接种猕猴中；（3）探索记忆NK细胞识别和特异性的细胞和分子机制。