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

• 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
• 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

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：没有有效的预防性HIV疫苗可以防止250万新的年度艾滋病毒感染。理想的疫苗将至少引起两种免疫力：减少病毒采集的抗体反应和CD8 T细胞对控制病毒复制的反应。有良好宿主HLA基因的人有足够的证据表明，特别有效的抗病毒CD8 T细胞反应保持了对病毒复制的特殊控制。大多数人群没有这些有利的HLA基因，因此我们需要设计方法来提高通常潜在的宿主免疫反应的有效性。循环的艾滋病毒序列之间也有巨大的多样性，但是基因组的功能和/或结构上重要的区域似乎不容易忍受突变。没有证据表明，在没有保护性HLA基因的宿主中，CD8 T细胞反应可以有效地靶向这些较小的病毒序列。建立构成或“不变”表位的价值（或缺乏价值） 疫苗既及时又非常重要。 具有相同主要的组织相容性复合物（MHC）I遗传学的毛里求利亚cynomolgus猕猴（MCM）可预测且可重复可再现的邻苯二醇免疫缺陷病毒（SIV）特定CD8 T细胞反应。感染了SIVMAC239` NEF的MCM维持极低的病毒血症，可以被认为是HIV“精英控制”的MHC独立模型。我们可以操纵感染的病毒序列，以“淘汰”不同T细胞表位的免疫原性，从而破坏病毒控制。在这项研究中，我们将尝试通过“敲除”靶向变量或不变表位的CD8 T细胞反应“敲除”动物中对具有不利遗传学的动物的精英控制。我们假设靶向构成或“不变”表位的CD8 T细胞没有有效检测和破坏几乎感染的细胞，而当这种CD8 T细胞可以在体外产生抗病毒细胞因子时，EVN。第一次，特异性 可以直接比较这些响应的质量，以了解最佳的CD8 T细胞反应，包括未来的疫苗。 我们的研究利用了一种创新的系统，在该系统中直接测试受保护的CD8 T细胞反应。尽管该项目的PI是一个新的研究者，但她已经研究了MCM中SIV发病机理和SIV特异性宿主免疫。她重大意识到，这些动物种群可用于清楚地定义针对这些不同类别表位的CD8 T细胞反应的价值。通过完成该项目，她将进一步证明使用MHC认同的MCM研究T细胞免疫和基于T细胞的疫苗，并继续开拓这一研究领域。