EIAV Envelope Variation and Vaccine Efficacy

EIAV 包膜变异和疫苗功效

• 批准号: 6760035
• 负责人: Ronald C Montelaro
• 金额: $ 61.67万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760035
• 关键词: Retroviridae disease; Venezuelan equine encephalitis virus; active immunization; adeno associated virus group; cellular immunity; drug screening /evaluation; equine infectious anemia virus; horses; humoral immunity; longitudinal animal study; macrophage; microorganism immunology; phenotype; protein sequence; tissue /cell culture; transfection /expression vector; viral vaccines; virus antigen; virus envelope; virus infection mechanism; virus protein

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.

描述（由申请人提供）：我们在过去二十年中利用马传染性贫血病毒（EIAV）系统开发了一项综合性多学科研究计划，以研究慢病毒在宿主免疫反应强劲的情况下持续存在的基本机制、保护性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免疫策略的评估。虽然慢病毒包膜变异已得到充分记录，但目前这种变异对疫苗功效的影响在很大程度上仍然是推测性的。在当前的申请中，我们建议检验以下假设：EIAV Env 是疫苗功效的主要决定因素，有效的疫苗必须针对保守的免疫隐性 Env 决定因素引发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，我们建议 Env 免疫原的性质及其呈现方法都会影响疫苗的免疫特异性和功效，并且必须优化这两个参数。因此，提出以下具体目标： (i) 确定地理上不同的初级分离株的 Env 蛋白的体液和细胞免疫决定因素，并评估确定的序列变异对免疫原性和抗原特性的影响； (ii) 直接检查确定的初级包膜变异对实验性 EIAV 疫苗的保护作用，此前已证明该疫苗对同源病毒攻击具有保护作用； (iii) 开发和评估使用 VEE 和 AAV 病毒载体的新型免疫策略，以引发针对不同 EIAV 攻击的持久广泛保护性疫苗免疫力。预计拟议研究的结果将为确定的自然 Env 变异对免疫表型的影响、攻击 Env 变异与疫苗功效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 研究的结果应该与其他动物慢病毒系统中正在进行的疫苗研究相补充，并与候选人类艾滋病疫苗的设计和评估相关。