Equine Infectious Anemia Virus Envelope Variation and Vaccine Efficacy

描述（由申请人提供）：在过去的二十年中，我们开发了一个综合的多学科研究项目，利用马传染性贫血病毒（EIAV）系统来研究慢病毒在强大的宿主免疫反应下持续存在的基本机制，保护和增强病毒特异性免疫的性质，以及作为HIV-1/ aids疫苗开发模型的实验性免疫策略的评估。虽然慢病毒包膜变异有很好的文献记载，但这种变异对疫苗效力的影响目前在很大程度上仍是推测性的。在当前的应用中，我们建议检验以下假设，即EIAV环境因子是疫苗效力的主要决定因素，有效的疫苗必须对保守的免疫隐性环境因子引起适当的体液和细胞免疫反应，以提供持久的广泛保护性免疫。此外，我们认为Env免疫原的性质及其呈递方法都会影响疫苗的免疫特异性和有效性，这两个参数都必须优化。因此，提出了以下具体目标：(i)确定地理上不同的初级分离株Env蛋白的体液和细胞免疫决定因素，并评估确定的序列变化对免疫原性和抗原特性的影响；㈡直接审查确定的初级包膜变异对先前证明对同源病毒攻击具有保护作用的实验性EIAV疫苗的保护作用；（iii）开发和评估使用VEE和AAV病毒载体的新型免疫策略，以引发针对各种EIAV挑战的持久广泛保护性疫苗免疫。预计拟议研究的结果将为确定的自然环境变异对免疫表型的影响，挑战环境变异与疫苗效力的关系以及病毒载体疫苗实现保护性免疫的潜力提供新的见解。因此，这些EIAV研究的结果应该是对正在进行的其他动物慢病毒系统疫苗研究的补充，并与设计和评价候选人类艾滋病疫苗有关。

DESCRIPTION (provided by applicant): We have during the past twenty years developed a comprehensive multidisciplinary research program using the equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses persist despite robust host immune responses, the nature of protective and enhancing virus-specific immunity, and the evaluation of experimental immunization strategies as models for HIV-1/AIDSvaccine development. While Lentivirus envelope variation is well documented, the impact of this variation on vaccine efficacy remains largely speculative at this time. In the current application we propose to examine the hypothesis that the EIAV Env is the primary determinant of vaccine efficacy and that effective vaccines must elicit appropriate humoral and cellular immune responses to conerved immunorecessive Env determinants to provide enduring broadly protective immunity. Moreover, we suggest that both the nature of the Env immunogen and its method of presentation affect vaccine immune specificity and efficacy and that both parameters must be optimized. Thus, the following specific aims are proposed: (i) To define the humoral and cellular immune determinants of Env proteins of geographically diverse primary isolates and to assess the effects of defined sequence variation on immunogenic and antigenic properties; (ii) To examine directly the role of defined primary envelope variations on protection by experimental EIAV vaccines previously shown to be protective to homologous virus challenge; and (iii) To develop and evaluate novel immunization strategies using VEE and AAV viral vectors to elicit enduring broadly protective vaccine immunity to diverse EIAV challenge. It is anticipated that the results of the proposed studies will provide novel insights into the impact of defined natural Env variation on immune phenotypes, the relationship of challenge Env variation to vaccine efficacy, and the potential for viral vector vaccines to achieve protective immunity. Thus, the results of these EIAV studies should be complementary to ongoing vaccine studies in other animal lentivirus systems and relevant to the design and evaluation candidate human AIDS vaccines.