Development and Analysis of Replication-Deficient CMV Vectors

复制缺陷型 CMV 载体的开发和分析

• 批准号: 8117930
• 负责人: Klaus J Fruh
• 金额: $ 43.54万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117930
• 关键词: AIDS Vaccines; AIDS/HIV problem; Acute; Adult; Animal Model; Animals; Antigens; Attenuated; Characteristics; Clinical Trials; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Economic Inflation; Essential Genes; Future; Genes; Genome; Goals; Growth; HIV; HIV vaccine; Human; Immune; Immune response; Immunity; Immunization; Immunocompromised Host; Immunosuppression; In Vitro; Individual; Infection; Instruction; Macaca mulatta; Maintenance; Memory; Modeling; Murid herpesvirus 1; Mus; Outcome Study; Pathogenesis; Pathogenicity; Performance; Population; Pregnant Women; Preparation; Principal Investigator; Production; Proteins; Publishing; Recombinant Vaccines; Recombinants; Role; SIV; Safety; Site; Stem cell transplant; Surface; T cell response; T memory cell; T-Lymphocyte; Testing; Vaccines; Viral; Viral Antigens; Viral Pathogenesis; Virus; Virus Diseases; Virus Shedding; attenuation; base; design; fetal; immunogenicity; in vivo; in vivo Model; insight; latent infection; novel; prevent; response; vector

Cytomegalovirus (CMV)-based vectors are uniquely capable of inducing longterm effector memory T cell responses and escaping vector-specific immunity. However, fully replicative vectors are unlikely to be approved for human use given the pathogenic potential of CMV, particularly in pregnant women and immunocompromised individuals. A central goal is therefore to increase vector safety while maintaining immunogenicity and efficacy. In this project, we will define how acute and persistent replication correlates with the ability of rhesus CMV to induce a T cell response to simian immunodeficiency virus (SIV). Preliminary data suggest that severely attenuated RhCMV can still induce CMV-specific immune responses in sero-negafive animals consistent with persistent antigen production. Unlike the parental vector however, the such low-cycle vectors do not seem to be secreted from inoculated animals. Importanfiy, low-cycle vectors expressing simian immunedeficiency virus (SIV) antigens super-infect sero-positive animals and induce an SIV-specific T cell response suggesfing retention of immunogenicity. In three specific aims we will determine the extent to which vectors can be rendered replication-incompetent without sacrificing immunogenicity and the pathogenicity of such vectors in the immunocompromised. Specific Aim 1 is to further reduce the ability of RhCMV/SIV vectors to replicate by construcfing single-cycle vectors. In addifion, we will construct vectors whose replication can be externally controlled thus allowing us to study the role of viral replicafion and spreading for the establishment and maintenance of persistent anfigen producfion and T cell stimulation. Specific Aim 2 is to determine the pathogenicity of replicafion-deficient vectors in an animal model of congenital infecfion. A further aim is to compare their ability to induce robust SIV-specific effector memory T cell responses in sero-positive animals. Specific Aim 3 is to generate vectors combining the lowest pathogenicity with the highest immunogenicity for efficacy studies and to confirm that corresponding human CMV vectors are attenuated in a novel animal model of latent infection. Thus, we expect that the attenuation strategy developed here will be direcfiy translatable into HCMV/HIV vectors. RELEVANCE (See instructions): The goal of this project is to increase the safety of an HIV vaccine delivered by cytomegalovirus. This will be achieved by removing essential genes from the cytomegalovirus genome thus generating a replicafion- deficient vaccine. We will test whether the resulfing vaccine is safe while retaining the advantageous immunizing characteristics of the replicating vaccine. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Perfonmance Site Fomnat Page) Project/Performance

基于巨细胞病毒（CMV）的载体独特地能够诱导长期效应记忆T细胞 反应并逃避媒介特异性免疫。然而，完全复制的载体不太可能 鉴于CMV的致病潜力，特别是在孕妇中， 免疫力低下的人。因此，一个中心目标是提高病媒安全性，同时维持 免疫原性和功效。在本项目中，我们将定义急性复制和持久复制如何相互关联 具有恒河猴CMV诱导对猿猴免疫缺陷病毒（SIV）的T细胞应答的能力。 初步数据表明，严重减毒的RhCMV仍然可以诱导CMV特异性免疫应答 在血清阴性动物中与持续抗原产生一致。然而，与亲本载体不同， 这种低循环载体似乎不从接种的动物中分泌。重要的是，低周期 表达猴免疫缺陷病毒（SIV）抗原的载体超感染血清阳性动物， 诱导SIV特异性T细胞应答，从而保持免疫原性。在三个具体目标中， 确定在多大程度上可以使载体不能复制，而不牺牲 免疫原性和这种载体在免疫受损的人中的致病性。具体目标1是 通过构建单循环载体进一步降低RhCMV/SIV载体的复制能力。此外， 我们将构建载体，其复制可以外部控制，从而使我们能够研究的作用， 病毒复制和传播，以建立和维持持续的ANFIGEN生产和T 细胞刺激具体目标2是确定复制缺陷型载体在动物中的致病性 先天性感染的模型。进一步的目的是比较它们诱导强大的SIV特异性效应物的能力， 血清阳性动物的记忆T细胞应答。具体目标3是生成组合 最低致病性和最高免疫原性用于有效性研究，并确认相应的 人CMV载体在新型潜伏感染动物模型中减毒。因此，我们预计， 在此开发的减毒策略将可直接转化到HCMV/HIV载体中。 相关性（参见说明）： 该项目的目标是提高巨细胞病毒提供的艾滋病毒疫苗的安全性。这将是 通过从巨细胞病毒基因组中去除必需基因从而产生复制来实现， 缺陷疫苗我们将在保留疫苗优点的同时， 复制型疫苗的免疫特性。 项目/绩效现场（如果需要额外空间，请使用项目/绩效现场表格页面） 项目/业绩