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）的载体具有唯一能够诱导长期效应器记忆T细胞 反应和逃避矢量特异性免疫力。但是，完全重复的向量不太可能 鉴于CMV的致病潜力，特别是在孕妇和 免疫功能低下的个体。因此，一个中心目标是提高向量安全性的同时保持 免疫原性和功效。在这个项目中，我们将定义急性和持久复制如何相关 CMV的能力诱导T细胞对猿猴免疫缺陷病毒（SIV）的反应。 初步数据表明，严重减弱的RHCMV仍然可以诱导CMV特异性免疫反应 在与持续的抗原产生一致的血清阴力动物中。但是，与父母矢量不同， 这样的低循环矢量似乎并未从接种动物中分泌。 eximentanfiy，低周期 表达猿类免疫缺陷病毒（SIV）抗原超级感染血清阳性动物的载体和 诱导SIV特异性T细胞反应建议保留免疫原性。在三个具体目标中，我们将 确定可以在多大程度上渲染复制的媒介而不牺牲的程度 免疫功能低下的载体的免疫原性和致病性。具体目标1是 进一步降低了RHCMV/SIV矢量通过约束单周期向量复制的能力。中添， 我们将构建可以在外部控制复制的向量，从而使我们能够研究 病毒式复制和扩散，以建立和维护持续的过性生产和T 细胞刺激。具体目的2是确定动物中副业缺陷载体的致病性 先天性不合理的模型。另一个目的是比较他们诱导SIV特异性效应器的能力 血清阳性动物的记忆T细胞反应。特定目的3是生成组合的向量 最低的致病性具有最高的免疫原性，以进行疗效研究，并确认相应 人CMV载体在一种新型的潜在感染动物模型中减弱。因此，我们期望 此处开发的衰减策略将是可转换为HCMV/HIV媒介的。 相关性（请参阅说明）： 该项目的目的是提高巨细胞病毒传递的HIV疫苗的安全性。这将是 通过从巨细胞病毒基因组中去除基本基因而实现的，从而产生了复制法 - 疫苗不足。我们将测试重建疫苗是否安全，同时保留有利的疫苗 复制疫苗的免疫特征。 项目/穿越稳定站点（如果需要额外的空间，请使用Project/PertonMance网站FOMNAT页面） 项目/性能