POXVIRUS SCR-CONTAINING PROTEINS AS THERAPEUTIC TARGETS

痘病毒含 SCR 蛋白作为治疗靶点

基本信息

批准号：
6637845
负责人：
Stuart N. Isaacs
金额：
$ 29.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2004-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6637845
关键词：
Poxviridae Poxviridae disease bioterrorism /chemical warfare cooperative study laboratory mouse monoclonal antibody nonhuman therapy evaluation protein structure function vaccine development vaccinia virus virus protein

项目摘要

The ability to vaccinate an at-risk civilian population with vaccinia virus is central to preparing for the potential threat of smallpox bioterrorism. However, a critical limitation of this strategy is the recognized complications of vaccinia vaccination, particularly in immunocompromised hosts, pregnant women, and infants. Therapeutic interventions currently available to counter such complications are inadequate and novel strategies are needed. We propose to develop such new therapies that target related, yet functionally distinct, vaccinia proteins. The vaccinia complement-control protein (VCP) and the extracellular enveloped virus (EEV)-specific B5R protein both contain short consensus repeat (SCR) units present in complement regulatory proteins. We have shown that VCP and the B5R proteins are critical for pathogenesis in vivo. VCP inhibits complement activation and helps the virus evade the host complement mediated attack. The B5R protein is essential for efficient viral dissemination. Our hypothesis is that these viral SCR-containing proteins have critical functions in pathogenesis that make them uniquely suited to serve as novel targets for therapeutic strategies directed at complications occurring during vaccinia immunization. Individuals with life-threatening vaccinia virus vaccine complications usually have defective cell-mediated or humoral immunity, but typically have intact innate immune function. A therapeutic inhibitor of VCP's complement control activity would therefore be a novel approach to managing vaccinia vaccine complications because such an inhibitor would allow the host's innate immune system to regain control of the infection. In Specific Aim number 1, we will utilize phage library display to identify specific inhibitors of VCP that prevent its inhibition of the complement cascade. The B5R protein is one of several EEV-specific proteins. B5R also contains SCRs and, while complement regulatory activity has not been identified, we and others have demonstrated that B5R is critical for EEV formation and viral spread in vivo. In addition, recent reports have shown that B5R is one of the principal targets for EEV neutralizing antibodies. Thus, therapeutic targeting of B5R offers an additional way of controlling vaccinia virus replication and dissemination. In Specific Aim number 2 we will develop monoclonal antibodies (mAbs) to the B5R protein and identify mAbs that neutralize EEV. We believe that identification of such mAbs (along with a cocktail of humanized mAbs to other EEV-specific proteins) can form the basis for a passive immune neutralization strategy to control vaccinia virus vaccine complications. We anticipate that these proteins will provide novel targets for immunomodulation of vaccinia virus. In addition, because both VCP and BSR are present in variola virus, these new therapies may be effective against smallpox infection.

疫苗病毒接种疫苗的平民接种能力对于准备天花生物恐怖主义的潜在威胁至关重要。但是，该策略的关键局限性是疫苗接种的公认并发症，特别是在免疫功能低下的宿主，孕妇和婴儿中。目前可用于抵抗此类并发症的治疗干预措施不足，需要新颖的策略。我们建议开发这种靶向相关但功能不同的疫苗蛋白的新疗法。疫苗补体 - 对照蛋白（VCP）和细胞外包膜病毒（EEV）特异性B5R蛋白都包含补体调节蛋白中存在的短共识重复（SCR）单位。我们已经表明，VCP和B5R蛋白对于体内发病机理至关重要。 VCP抑制补体激活，并帮助病毒逃避宿主补体介导的攻击。 B5R蛋白对于有效的病毒传播至关重要。我们的假设是，这些含有病毒SCR的蛋白质在发病机理中具有关键功能，使它们非常适合作为针对疫苗免疫过程中发生并发症的治疗策略的新靶标。患有威胁生命的疫苗病毒疫苗并发症的个体通常具有缺陷的细胞介导或体液免疫，但通常具有完整的先天免疫功能。因此，VCP补体控制活性的治疗抑制剂将是一种管理疫苗疫苗并发症的新方法，因为这种抑制剂将使宿主的先天免疫系统重新控制感染。在特定的目标数字1中，我们将利用噬菌体库显示来识别VCP的特定抑制剂，以防止其抑制补体级联反应。 B5R蛋白是几种EEV特异性蛋白之一。 B5R还包含SCR，虽然尚未确定补体调节活性，但我们和其他人证明B5R对于在体内的EEV形成和病毒传播至关重要。此外，最近的报告表明，B5R是中和抗体的主要目标之一。因此，B5R的治疗靶向提供了控制疫苗病毒复制和传播的另一种方法。在特定目标2中，我们将开发针对B5R蛋白的单克隆抗体（mAb），并识别中和EEV的单克隆抗体。我们认为，鉴定此类mAB（以及其他EEV特异性蛋白质的人源化单元鸡尾酒）可以为控制疫苗病毒疫苗并发症的被动免疫中和策略构成基础。我们预计这些蛋白质将为疫苗病毒的免疫调节提供新的靶标。另外，由于VCP和BSR都存在于Variola病毒中，因此这些新疗法可能有效地针对天花感染。