ROLE OF CD4+ TH1 LYMPHOCYTES IN PROTECTION AGAINST EIAV

描述：(改编自申请者摘要)免疫识别 帮助控制马传染性贫血病毒(EIAV)的反应似乎 重要的是因为类似的机制可能适用于其他慢病毒 感染。假设免疫反应参与了 对EIAV的保护可以确定是基于对 马的疾病以及淋巴细胞反应是 负责控制。初发血浆病毒血症降至 在感染的马中检测不到的水平与出现 CD8细胞毒性T淋巴细胞(CTL)，而中和抗体通常是 直到血浆病毒血症清除后才能检测到。对以下方面的要求 病原体特异性Th1亚群的辅助T淋巴细胞(HTL)活性 由细胞因子的产生决定，对于有效的CTL反应是好的 有记录在案。此外，在不同的病毒系统中也有研究 证明只使用hTL表位就能激发强大的CD4的有效性 Th1应答以增强随后的增殖和CTL活性 病毒挑战。这种慢病毒疫苗的方法可能会克服 难以同时识别通用CTL和HTL表位 由广泛的主要组织相容性复合体I类或类 分别为II类分子。这是因为有证据表明 这种通用的HTL表位可能比通用的CTL表位更常见。 此外，htl表位位于慢病毒的保守区。 可能会绕过另一个关键的抗原性变异问题。我们的 长期的研究目标是确定HTL和CTL在控制中的作用 慢病毒感染，为了实现这个目标，我们特别需要更多 了解CD4T淋巴细胞在这种免疫中的作用。到那时候 最终，本提案中概述的实验将直接测试 假设诱导CD4Th1淋巴细胞对普适性和 保守的EIAV表位将促进增强的CTL应答，并负担 针对随后的EIAV挑战提供保护。

DESCRIPTION: (Adapted from Applicant's Abstract) Identification of immune responses that can help control equine infectious anemia virus (EIAV) seems important because similar mechanisms may be applicable to other lentivirus infections. Reasons for assuming that immunological responses involved in protection against EIAV can be identified are based on eventual control of the disease in horses and on the demonstration that lymphocyte responses are responsible for the control. The decrease of initial plasma viremia to undetectable levels in infected horses is associated with the appearance of CD8+ cytotoxic T lymphocytes (CTL), while neutralizing antibody often is undetectable until after clearance of the plasma viremia. The requirement for pathogen-specific CD4+ helper T lymphocyte (HTL) activity of the Th1 subset, as determined by cytokine production, for effective CTL responses is well documented. In addition, there are studies in different viral systems that demonstrate the efficacy of using only HTL epitopes that elicit a strong CD4+ Th1 response to enhance both proliferative and CTL activity upon subsequent virus challenge. Such an approach for lentivirus vaccines might overcome the difficulty of identifying both universal CTL and HTL epitopes which are presented by a broad range of major histocompatibility complex class I or class II molecules, respectively. This is because there is evidence indicating that such universal HTL epitopes may be more common than universal CTL epitopes. Further, HTL epitopes have been located in conserved regions of lentiviruses possibly circumventing another key problem of antigenic variation. Our long-term research goal is to determine the roles of HTL and CTL in the control of lentiviral infections and to achieve this goal we particularly need more knowledge of the contribution of CD4+ T lymphocytes to this immunity. To that end, the experiments outlined in this proposal will directly test the hypothesis that induction of CD4+ Th1 lymphocyte responses to universal and conserved EIAV epitopes will promote enhanced CTL responses to, and afford protection against, subsequent EIAV challenge.