Manipulation of immunodominance to promote heterosubtypic immunity to Influenza

描述(申请人提供)：本R21提案中概述的实验的主要目标是促进对流感病毒感染的异种亚型免疫。流感是一种重要的人类病原体，目前还没有可用于促进持久有效免疫的疫苗。这是最近一个特别紧迫的目标，因为出现了一种高致病性H5N1禽流感毒株，该毒株已传播给人类，造成了大流行的潜在威胁。最近，我们的实验室开发了一种新的成功的策略来操纵CD4T细胞反应中的免疫优势。在这项建议中，我们希望利用这一策略来探索故意关注CD4T细胞对流感亚型之间共享的表位的反应，特别是H5亚型中表达的表位，是否将促进保护性异亚型免疫。由于这些研究对人类疫苗设计的直接影响，我们将使用人类HLA-DR分子呈现的多肽和DR1转基因小鼠来进行这些实验。我们将获得新的HA多肽蛋白结构，以驱动CD4T细胞对血凝素表位的有意关注，血凝素表位在血清学上不同的HA亚型中高度保守。具体目的1：鉴定流感HA的免疫优势DR1限制性CD4T细胞表位。具体目标2：设计和利用HA衍生多肽的动力学稳定性变体来促进免疫优势。具体目标3.促进CD4T细胞对保守表位的应答和对病毒攻击的保护。

DESCRIPTION (provided by applicant): The major goal of the experiments outlined in this R21 proposal is to promote heterosubtypic immunity to influenza virus infection. Influenza is a significant human pathogen for which there is no available vaccine1 that promotes persistent and effective immunity. This is a particularly urgent objective of late because of the emergence of a highly pathogenic H5N1 strain of avian influenza that has passed to humans, creating a potential threat of a pandemic. Recently, our laboratory has developed a novel and successful strategy to manipulate immunodominance in CD4 T cell responses. In this proposal, we wish to use this strategy to explore whether intentional focus of the CD4 T cell response toward epitopes shared among subtypes of influenza, particularly those expressed within the H5 subtype, will promote protective heterosubtypic immunity. Because of the direct implication of these studies on human vaccine design, we will perform these experiments using peptides presented by human HLA-DR molecules and DR1-transgenic mice. We will derive novel HA peptide-containing protein constructs to drive intentional focus of the CD4 T cell response towards hemagglutinin epitopes that are highly conserved among serologically distinct HA subtypes. Specific Aim 1: Identification of immunodominant DR1-restricted CD4 T cell epitopes to influenza HA. Specific Aim 2: Design and utilize kinetic stability variants of HA-derived peptides to promote immunodominance. Specific Aim 3. Promoting focus of the CD4 T cell responses toward conserved epitopes and protection to virus challenge.