Evaluating immunity elicited by CD8 T Cell responses targeting invariant epitopes

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。一种理想的疫苗至少会引发两种免疫：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。从宿主HLA基因有利的人群中有充分的证据表明，特别有效的抗病毒CD8 T细胞反应维持了对病毒复制的特殊控制。大多数人没有这些有利的HLA基因，所以我们需要设计出方法来提高通常不太有效的宿主免疫反应的功效。在循环的HIV序列中也存在着巨大的多样性，但是基因组中一些功能和/或结构上重要的区域似乎不容易耐受突变。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不太可变的病毒序列。确定中的保守或“不变”表位的价值（或缺乏价值）

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.