HSV-2 immune evasion as a virulence factor

HSV-2 免疫逃避作为毒力因子

基本信息

批准号：
8695604
负责人：
Harvey Michael Friedman
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8695604
关键词：
Animal Model Animals Antibodies Antigens Binding Blocking Antibodies Cavia Childbirth Complement Complement 3b Complement Activation Disease Dose Effectiveness Endpoint Determination Fc domain Generations Genital system Glycoproteins HIV HIV Infections HIV-1 Health Health Benefit Herpes Simplex Virus Vaccines Herpesvirus 1 Human Human Herpesvirus 2 Immune Immune response Immunity Immunization Immunoglobulin G Individual Infant Infection Knock-out Lead Lesion Life Mediating Modeling Mus Passive Transfer of Immunity Pathogenesis Predictive Value Public Health Recurrence Risk Role Serum Severities Simplexvirus Spinal Ganglia Subunit Vaccines T cell response T-Lymphocyte Testing Tissues Ulcer Vaccine Antigen Vaccines Vagina Viral Antigens Virulence Virulence Factors Virulent Virus Virus Replication Work acquired immunity antibody-dependent cell cytotoxicity base emotional distress genital herpes glycoprotein C, herpes simplex virus type 2 glycoprotein D-herpes simplex virus type 2 human subject improved inhibiting antibody latent infection mortality mutant neutralizing antibody novel strategies prevent protein expression research study tool transmission process vaccine development vaccine efficacy virus culture

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus type 2 (HSV-2) infects a half-billion individuals worldwide, which has important public health implications since HSV-2 genital ulcer disease increases the risk of acquiring and transmitting HIV by 3-fold. Our work focuses on immune evasion strategies of HSV-2 glycoproteins C (gC2) and E (gE2). HSV-2 gC2 binds complement component C3b to inhibit complement activation. HSV-2 gE2 blocks Fc- mediated activities by binding the Fc domain of an IgG antibody molecule that is bound by its F(ab')2 domain to HSV antigen, which inhibits complement activation and antibody-dependent cellular cytotoxicity (ADCC). In Aim 1 we will evaluate the hypothesis that gC2 and gE2 immune evasion greatly reduce the effectiveness of an HSV-2 glycoprotein D (gD2) vaccine in humans by inhibiting antibody and complement, and that gC2 and gE2 immune evasion contribute to recurrent genital disease after naturally acquired infection. We will test our hypothesis by evaluating sera from subjects immunized with the GSK gD2 subunit vaccine to determine whether gC2 and gE2 immune evasion inhibit antibody and complement neutralization and ADCC, and by assessing sera obtained from subjects with multiple recurrences of genital HSV-2 or with no recurrences to evaluate the contribution of gC2 and gE2 immune evasion to recurrent genital ulcer disease. In Aim 2 we will assess the hypothesis that HSV-2 gC2 and gE2 mutant strains defective in immune evasion will be log10 orders of magnitude less virulent than wild-type or recue virus in mouse and guinea pig vaginal infection models. We will test our hypothesis by constructing single gC2 and gE2 mutant strains and a double gC2/gE2 mutant strain that are defective in immune evasion but intact for replication, protein expression and other functions ascribed to them. We will determine the magnitude of the impact of immune evasion in mice and guinea pigs and define mechanisms using complement and NK deficient animals. In Aim 3 we will evaluate the hypothesis that a gC2/gD2/gE2 vaccine totally protects against genital ulcer disease and markedly reduces or totally prevents latency. We will define the optimum dose of gC2 and gE2 antigen that induce high titers of antibodies that block immune evasion and of gD2 antigen that induces high titers of neutralizing antibodies. We will then evaluate whether the trivalent vaccine provides better protection against genital disease and latent infection than any single antigen or double antigen combination. To improve the translatability of animal models to human studies, we will modify endpoint determinations in animal models to match human trials, including confirming disease scores by seroconversion, PCR and culture. We will determine if local virus replication in vaginal tissues is sufficient to induce seroconversion in immunized animals that have no genital disease or latent infection. Detecting seroconversion under these conditions would be informative since it is may not serve as a useful marker for latency in human trials. These studies take a novel approach to vaccine development and may lead to a new generation of vaccines.

描述（由申请人提供）：单纯疱疹病毒2型（HSV-2）感染了全球五十亿个人，这具有重要的公共健康影响，因为HSV-2生殖器溃疡疾病会增加获得和传播HIV的风险3倍。我们的工作着重于HSV-2糖蛋白C（GC2）和E（GE2）的免疫逃避策略。 HSV-2 GC2结合补体组件C3b以抑制补体激活。 HSV-2 GE2通过结合由其F（AB'）2结构域与HSV抗原结合的IgG抗体分子的FC结构域来阻断FC介导的活性，后者抑制了补体激活和抗体依赖性细胞毒性（ADCC）。在目标1中，我们将评估以下假设：GC2和GE2免疫逃避可以大大降低HSV-2糖蛋白D（GD2）疫苗在人类中通过抑制抗体和补体的有效性，并且GC2和GE2免疫逃避自然产生了自然感染后复发性均质疾病。我们将通过评估用GSK GD2亚基疫苗免疫的受试者的血清来测试我们的假设，以确定GC2和GE2免疫逃避是否抑制了抗体，补体中和和ADCC，并通过评估来自GENITAL HSV-2-2或EDERINCE贡献GC2和GEC2的受试者从受试者中获得的Sera，并评估来自GC2和GEC2的多次复发。在AIM 2中，我们将评估以下假设：HSV-2 GC2和GE2突变体在免疫逃避中有缺陷的log10比野生型的毒气级别要比野生型的毒性低或在小鼠和豚鼠阴道感染模型中恢复病毒。我们将通过构建单个GC2和GE2突变菌株以及双GC2/GE2突变体菌株来检验我们的假设，该菌株在免疫逃避中有缺陷，但完好无损地复制，蛋白质表达和其他归因于它们的功能。我们将确定免疫逃避对小鼠和豚鼠的影响的大小，并使用补体和NK缺乏动物来定义机制。在AIM 3中，我们将评估以下假设：GC2/GD2/GE2疫苗完全可以防止生殖器溃疡疾病，并显着降低或完全阻止潜伏期。我们将定义GC2和GE2抗原的最佳剂量，这些剂量诱导较高的抗体滴度，这些抗体阻止免疫逃避和GD2抗原诱导中和抗体的高滴度。然后，我们将评估三价疫苗是否比任何单一抗原或双抗原组合都更好地保护对生殖器疾病和潜在感染。为了改善动物模型向人类研究的可翻译性，我们将修改动物模型中的终点测定以匹配人类试验，包括通过血清转化，PCR和培养确认疾病得分。我们将确定阴道组织中的局部病毒复制是否足以诱导没有生殖器疾病或潜在感染的免疫动物中的血清转化。在这些条件下检测血清转化将是有益的，因为它可能无法成为人类试验中潜伏期的有用标记。这些研究采用了一种新型的疫苗开发方法，并可能导致新一代疫苗。