Evaluating immunity elicited by CD8 T Cell responses targeting invariant epitopes

描述：目前还没有有效的预防性艾滋病毒疫苗来预防每年250万新的艾滋病毒感染。一种理想的疫苗应该至少诱导两种免疫：减少病毒获取的抗体反应和控制病毒复制的CD8 T细胞反应。来自具有有利宿主人类白细胞抗原基因的人的充分证据表明，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，所以我们需要设计方法来提高通常较弱的宿主免疫反应的有效性。流通中的艾滋病毒序列也存在巨大的多样性，但基因组的一些功能和/或结构上重要的区域似乎不容易容忍突变。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针对这些变异较小的病毒序列。确定保守的或不变的表位的价值(或缺乏价值) 疫苗既及时又意义重大。 毛里求斯食蟹猴(MCM)具有相同的主要组织相容性复合体(MHC)I类基因，可装载可预测和可复制的猴免疫缺陷病毒(SIV)特异性CD8 T细胞反应。感染了SIVmac239nef的MCM保持着极低的病毒血症水平，可以被认为是一种不依赖MHC的艾滋病毒精英控制模型。我们可以操纵感染病毒的序列，“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，我们将试图通过敲除针对可变或不变表位的CD8 T细胞反应，来打破SIVmac239nef在具有不利遗传学的动物中的精英控制。我们假设，以保守的或不变的表位为靶点的CD8T细胞不能有效地检测和摧毁病毒感染的细胞，即使这种CD8T细胞在体外可以产生抗病毒细胞因子。这是第一次，这种特殊性 这些反应的质量可以直接进行比较，目的是为了了解未来疫苗中包括的最佳CD8 T细胞反应。 我们的研究利用了一种创新的系统，在该系统中直接测试保护性CD8 T细胞反应。虽然本项目的PI是一名新的研究者，但她已经在MCM中研究了SIV的致病机制和SIV特异性宿主免疫六年。她重要的认识到，这个动物种群可以用来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。通过完成这一项目，她将进一步展示使用MHC相合的MCM研究T细胞免疫和基于T细胞的疫苗的价值，并继续开拓这一领域的研究。

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.