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Eliciting neutralizing antibodies against the HCV E2 envelope glycoprotein

引发针对 HCV E2 包膜糖蛋白的中和抗体

基本信息

批准号：
7640900
负责人：
TATJANA DRAGIC
金额：
$ 20.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Approximately 3% of the world population is infected with the Hepatitis C virus (HCV). As a major cause of serious liver disease, HCV represents an urgent public health problem. Licensed antiviral therapies are non-specific and there is currently no vaccine against HCV. It has been shown that the humoral response predominantly target the E2 envelope glycoproteins. In order to escape from recognition by neutralizing antibodies, HCV has evolved glycosylation sites that obscure functionally critical sites on E2. These glycans also probably attenuate the ability of the immune system to effectively elicit neutralizing antibodies against the critical epitopes that they obscure. We recently showed that removal of certain glycosylation sites in the HCV E2 envelope glycoprotein generates a virus that is hyper-sensitive to neutralization by HCV+ patient sera. Two of the glycans were found to mask the highly conserved CD81 coreceptor binding site. We hypothesize that immunizing mice with these E2 glycosylation mutants, coupled with strategies that non-specifically boost innate immunity, will focus the humoral response on the CD81 binding site thereby eliciting high titers of broadly reactive neutralizing antibodies. Such antibodies are rare when elicited by wild type E2 wherein the CD81 binding site is occluded. In Specific Aim 1 we will immunize mice with glycosylation mutants of the recombinant soluble E2 protein formulated in various adjuvants. The resulting immune sera will be characterized for potency and breadth of neutralization. In Specific Aim 2 neutralizing monoclonal antibodies (MAbs) will be derived from animals with the highest neutralizing serum titers. Combinations of MAbs will be tested for synergy in their ability to inhibit viral entry. We will also determine whether neutralization correlates with MAb inhibition of E2-CD81 binding. In Specific Aim 3 we will determine which neutralizing sera, MAbs or combinations of MAbs can attenuate or prevent outgrowth of viral escape variants. Our work will have broad implications for designing vaccines to specifically block HCV infection. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) is a leading cause of life-threatening liver disease. We seek to design candidate vaccines to specifically block HCV infection.

描述（由申请人提供）：大约3%的世界人口感染丙型肝炎病毒（HCV）。作为严重肝病的主要原因，HCV代表了一个紧迫的公共卫生问题。许可的抗病毒治疗是非特异性的，目前没有针对HCV的疫苗。已经表明，体液应答主要靶向E2包膜糖蛋白。为了逃避中和抗体的识别，HCV已经进化出糖基化位点，这些位点掩盖了E2上的功能关键位点。这些聚糖还可能减弱免疫系统有效地引发针对它们掩盖的关键表位的中和抗体的能力。我们最近发现，在HCV E2包膜糖蛋白中某些糖基化位点的去除产生了一种对HCV+患者血清中和超敏感的病毒。发现两个聚糖掩盖高度保守的CD 81辅助受体结合位点。我们假设用这些E2糖基化突变体免疫小鼠，再加上非特异性增强先天免疫的策略，将使体液应答集中在CD 81结合位点，从而引发高滴度的广泛反应性中和抗体。当由其中CD 81结合位点被封闭的野生型E2引发时，这样的抗体是罕见的。在具体目标1中，我们将用在各种佐剂中配制的重组可溶性E2蛋白的糖基化突变体免疫小鼠。将表征所得免疫血清的中和效力和宽度。在特定目的2中，中和单克隆抗体（MAb）将来自具有最高中和血清滴度的动物。将测试MAb的组合在抑制病毒进入的能力方面的协同作用。我们还将确定中和是否与E2-CD 81结合的MAb抑制相关。在特定目标3中，我们将确定哪些中和血清，单克隆抗体或单克隆抗体的组合可以减弱或防止病毒逃逸变体的生长。我们的工作将对设计特异性阻断HCV感染的疫苗产生广泛的影响。公共卫生相关性：丙型肝炎病毒（HCV）是危及生命的肝脏疾病的主要原因。我们寻求设计候选疫苗来特异性阻断HCV感染。