Evaluating immunity elicited by CD8 T Cell responses targeting invariant epitopes

评估针对不变表位的 CD8 T 细胞反应引发的免疫

基本信息

批准号：
8658217
负责人：
SHELBY L OCONNOR
金额：
$ 70.19万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-05 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658217
关键词：
Alleles Animals Antibody Formation Antigens Antiviral Agents Area Blood CD8B1 gene Categories Cells Characteristics Communities Epitopes Frequencies Future Genetic Genome HIV HIV Infections HIV vaccine Haplotypes Immune Immune response Immunity Immunologics In Vitro Individual Investments Knock-out Macaca Major Histocompatibility Complex Modeling Monkeys Mutation Play Population Qualifying Reaction Time Relative (related person)Research Research Personnel Role SIV Shapes Specificity Stream System T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Time Vaccine Design Vaccines Variant Viral Viremia Virus Virus Replication Work arm base coping cytokine deep sequencing design human leukocyte antigen gene immunogenicity improved in vivo innovation insight mutant novel prevent prophylactic public health relevance research study response vector vaccine virus pathogenesis

项目摘要

DESCRIPTION: There is no effective prophylactic HIV vaccine to prevent the 2.5 million new annual HIV infections. An ideal vaccine would elicit at least two kinds of immunity: antibody responses to reduce viral acquisition and CD8 T cell responses to control virus replication. There is ample evidence, from people with favorable host HLA genes, that particularly effective antiviral CD8 T cell responses maintain exceptional control of virus replication. Most of the population does not have these favorable HLA genes, so we need to devise ways to improve the efficacy of typically less potent host immune responses. There is also enormous diversity among circulating HIV sequences, but some functionally and/or structurally important regions of the genome do not appear to easily tolerate mutations. There is no evidence that CD8 T cell responses, in a host without protective HLA genes, can effectively target these less variable viral sequences. Establishing the value (or lack thereof) of conserved, or 'invariant,' epitopes in a vaccine is both timely and highly significant. Mauritian cynomolgus macaques (MCM) with identical major histocompatibility complex (MHC) class I genetics mount predictable and reproducible simian immunodeficiency virus (SIV) specific CD8 T cell responses. MCM infected with SIVmac239¿nef maintain extremely low levels of viremia, and can be considered an MHC-independent model of HIV 'elite control.' We can manipulate the infecting viral sequence to 'knock out' the immunogenicity of different T cell epitopes, and thus break viral control. In this study, we will try to break elite control of SIVmac239¿nef in animals with unfavorable genetics by 'knocking out' either the CD8 T cell responses targeting variable or invariant epitopes. We hypothesize that CD8 T cells that target conserved or 'invariant' epitopes do not efficiently detect and destroy virally- infected cells, evn when such CD8 T cells can produce antiviral cytokines in vitro. For the first time, the specificity and quality of these responses can be compared directly, with an aim towards understanding the best CD8 T cell responses to include in future vaccines. Our study makes use of an innovative system in which to directly test protective CD8 T cell responses. Although the PI of this project is a new investigator, she has studied SIV pathogenesis and SIV specific host immunity in MCM for six years. She made the important realization that this population of animals can be used to clearly define the value of CD8 T cell responses targeting these different categories of epitopes. By completing this project, she will further demonstrate the value of using MHC-identical MCM to study T cell immunity and T cell based vaccines and continue to pioneer this area of research.

描述：目前还没有有效的预防性 HIV 疫苗能够预防每年 250 万例新的 HIV 感染。理想的疫苗至少会引发两种免疫：减少病毒获得的抗体反应和控制病毒复制的 CD8 T 细胞反应。来自具有有利宿主 HLA 基因的人的证据表明，特别有效的抗病毒 CD8 T 细胞反应可维持对病毒复制的特殊控制，大多数人群不具有这些有利的 HLA 基因，因此我们需要设计方法来提高其功效。通常，宿主免疫反应的效力较差。循环的 HIV 序列也存在巨大的多样性，但基因组的一些功能和/或结构重要区域似乎不容易耐受突变。没有证据表明宿主体内有 CD8 T 细胞反应。没有保护性 HLA 基因，可以有效地靶向这些变异较小的病毒序列，从而确定保守或“不变”表位的价值（或缺乏）。疫苗的出现既及时又非常重要。具有相同主要组织相容性复合物 (MHC) I 类遗传学的毛里求斯食蟹猴 (MCM) 会产生可预测且可重复的猿猴免疫缺陷病毒 (SIV) 特异性 CD8 T 细胞反应，感染了 SIVmac239¿ nef 维持极低水平的病毒血症，并且可以被认为是 HIV“精英控制”的 MHC 独立模型。我们可以操纵感染病毒序列来“敲除”不同 T 细胞表位的免疫原性，从而打破病毒控制。在这项研究中，我们将尝试打破 SIVmac239 的精英控制¿通过“敲除”针对可变或不变表位的 CD8 T 细胞反应，我们发现，针对保守或“不变”表位的 CD8 T 细胞不能有效地检测和破坏病毒感染的细胞。这种CD8 T细胞首次可以在体外产生抗病毒细胞因子。可以直接比较这些反应的质量，旨在了解未来疫苗中包含的最佳 CD8 T 细胞反应。我们的研究利用了一种创新系统来直接测试保护性 CD8 T 细胞反应。虽然该项目的 PI 是一位新研究者，但她已经研究了 MCM 中的 SIV 发病机制和 SIV 特异性宿主免疫。通过完成这个项目，她将进一步证明使用 MHC 相同的 MCM 来研究 T 细胞免疫和 T 细胞的价值。基于细胞的疫苗并继续开创这一研究领域。