VACCINIA B5R PROTEIN IN SPREAD IMMUNE EVASION, VACCINES

描述：（改编自申请人的摘要）牛痘病毒是本发明的焦点。 作为用于表达系统、基因递送、疫苗接种 并作为病毒发病机理的模型。然而， 利用牛痘载体的能力与致病性有关。研究 牛痘如何传播和逃避宿主免疫反应，以及如何 因此，增强表达抗原的免疫原性对于免疫原性是必需的。 有效利用这一载体系统。牛痘B5 R基因编码一种 42-在细胞外病毒体的膜上发现的kDa蛋白， 细胞在初步研究中，我们已经表明B5 R在以下方面起着关键作用： 细胞间传播和病毒通过 细胞外包膜病毒（EEV）的形成。此外，B5 R 细胞外结构域包含重复单元，与补体调节同源， 这些蛋白质可能参与病毒逃避宿主免疫应答。 然而，我们发现这个结构域和胞质尾区都是 为EEV的形成，因此可以用作网站， 异源抗原表达。我们假设B5 R是一种多功能的 一种在牛痘发病、传播和 逃避宿主免疫反应;通过B5 R的修饰，这些在体内 牛痘的特性可以改变; B5 R可以被操纵， 将异源抗原运输到EEV，产生牛痘载体， 增强免疫力。这项研究的目的是为了更好地了解 多功能B5 R蛋白在牛痘致病中的作用，并将其开发用于 异源蛋白表达，以产生基于牛痘的疫苗， 新的生物和抗原呈递能力。为此，我们将：1） 确定B5 R结构域在牛痘发病机制中的功能意义， 体内; 2）鉴定B5 R的补体调节特性;和3）确定 对新的牛痘疫苗产生的免疫应答， 与B5 R融合的HIV抗原 我们预期这些研究将深入了解牛痘的发病机制 以及B5受体在传播和逃避宿主免疫应答中的作用; 提供调节牛痘载体致病性的机制;和 提供了独特的疫苗抗原表达方法， 用于新的疫苗策略。

DESCRIPTION: (Adapted from Applicant's Abstract) Vaccinia virus is the focus of much attention as a vector for expression systems, gene delivery, vaccination, and as a model for viral pathogenesis. However, a major limitation in the ability to utilize vaccinia vectors are concerns about pathogenicity. The study of how vaccinia spreads and evades the host immune response as well as ways to enhance the immunogenicity of expressed antigens, is thus essential for the effective utilization of this vector system. The vaccinia B5R gene encodes a 42-kDa protein found on the membranes of extracellular virions and infected cells. In preliminary studies, we have shown that B5R plays a critical role in cell-to-cell spread and long range dissemination of the virus through the formation of the extracellular enveloped virus (EEV). In addition, the B5R extracellular domain contains repeat units, homologous to complement regulatory proteins, which may be involved in viral evasion of host immune responses. However, we showed that both this domain and the cytoplasmic tail are dispensable for EEV formation and therefore may be utilized as sites for heterologous antigen expression. We hypothesize that B5R is a multifunctional protein that plays a central role in vaccinia pathogenesis, dissemination, and evasion of host immune responses; that by modification of B5R, these in vivo properties of vaccinia can be altered; and that B5R can be manipulated to traffic heterologous antigens to EEV resulting in vaccinia vectors that generate enhanced immunity. The aim of this study is to better understand the multifunctional B5R protein in vaccinia pathogenesis and exploit it for heterologous protein expression in order to create vaccinia-based vaccines with novel biological and antigen presentation capabilities. To do this we will: 1) define the functional significance of B5R domains for vaccinia pathogenesis in vivo; 2) identify the complement regulatory properties of B5R; and 3) Determine the immune responses generated to novel vaccinia vaccines engineered to express an HIV antigen fused to B5R. We anticipate that these studies will give insight into vaccinia pathogenesis and the role of B5R in dissemination and evasion of host immune responses; provide a mechanism of modulating the pathogenicity of vaccinia vectors; and offer unique approaches to vaccinia-based antigen expression that can be exploited for novel vaccine strategies.