Self-limiting, and Dominant-negative Herpes Simplex Virus Recombinants

自限性和显性阴性单纯疱疹病毒重组体

• 批准号: 7151456
• 负责人: FENG YAO
• 金额: $ 31.36万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151456
• 关键词: Adult; Antibody Formation; Antigens; Appendix; Applications Grants; Binding Proteins; Biological Assay; CD80 Antigens; CD80 gene; CD8B1 gene; Cells; Cellular Immunity; Cessation of life; Characteristics; Class; Clinical; DNA biosynthesis; Defective Viruses; Dendritic Cells; Development; Disease Outbreaks; Dominant-Negative Mutation; Dose; Down-Regulation; Early Promoters; Effectiveness; Ensure; Evaluation; Exhibits; Facility Construction Funding Category; Generations; Genes; Genetic Engineering; Genome; Glycoproteins; Goals; Herpes Simplex Virus Vaccines; Herpesvirus 1; Human; Human Herpesvirus 2; Immune; Immune response; Immunity; In Vitro; Incidence; Individual; Infection; Investigation; Kinetics; Lead; Life; Mediating; Methodology; Modeling; Mus; Normal Cell; Numbers; Pharmaceutical Preparations; Play; Population; Prevention; Principal Investigator; Recombinants; Recurrence; Research; Research Personnel; Role; Safety; Simplexvirus; Switch Genes; T-Lymphocyte; Tetracycline; Tetracyclines; Therapeutic; Vaccinated; Vaccination; Vaccines; Viral; Viral Proteins; Viral Vaccines; Virus; Virus Diseases; Virus Replication; base; concept; cytotoxicity; immunogenicity; insight; latent infection; mouse model; mutant; neutralizing antibody; novel; novel strategies; polypeptide; prevent; programs; promoter; prophylactic; prototype; recombinant virus; recombinant virus vaccine; response; skin disorder; success; therapeutic vaccine; vector vaccine

DESCRIPTION (provided by applicant): Safety and efficiency in eliciting an effective host immune response are the two major criteria in developing recombinant viral vaccines against wild-type viral infections. An ideal recombinant viral vaccine should not only be replication-defective and capable of eliciting a broad protective immune response, but should also encode a safety mechanism that can inhibit de novo replication of naturally occurring wild-type virus if encountered within the same cells in the host. Herpes simplex virus (HSV) infections can cause significant clinical problems and even death in individuals who are immunodeficient or suffering from disorders of skin integrity. Approximately 63% of adults in the U.S are infected by HSV. Currently, there is no effective medication that can prevent primary HSV infections nor decrease the incidence of recurrences. Thus, there is a great need for developing a safe and effective HSV vaccine. We recently generated a prototype HSV recombinant virus, CJ83193, which is capable of inhibiting its own replication as well as that of wild-type HSV-1 and HSV-2. On the basis that CJ83193 can serve as a prophylactic vaccine against HSV-1 primary infection in mice at levels comparable to that of wild-type HSV-1 and that CJ83193 has shown great potential as a therapeutic vaccine to reduce recurrent infection, the overall objective of this research program is to further characterize and develop a new class of CJ83193-derived HSV recombinants whose safety and efficacy as vaccines against HSV infection can be greatly enhanced. Several novel approaches will be employed and developed in this grant application. Specific Aim 1 will focus on the development of CJ83193-1ike HSV recombinants with increased safety features and efficacy in blocking wild-type HSV viral DNA replication. The potential of these HSV recombinants as effective vaccines against HSV infection in mouse models will be evaluated in Specific Aim 2. Given that CJ83193 expresses a very low level of HSV-1 major antigen glycoprotein gD and, like other well-known replication-defective HSV recombinant viral vaccines, is incapable of expressing gC, another HSV-encoded major glycoprotein and a major target for CD4+ CTL, the goal of Specific Aim 3 is to enhance the efficacy of CJ83193-derived recombinant HSV vaccines with a gene switch that could lead to high-level expression of gD and/or gC in the vaccinated host. Recall that B7 costimulation plays a central role in the generation of anti-HSV-specific cellular immunity and T-cell-dependent antibody responses as well as infection of immature DC by HSV-1 leading to down-regulation of the expression of B7-1 and B7-2. Specific Aim 4 will focus on investigating the influence of de novo expression of B7-1 and B7-2 by HSV-1 replication-defective vaccine virus on the augmentation of host immunity against HSV infection.

描述（由申请人提供）： 安全性和引发有效宿主免疫反应的效率是开发针对野生型病毒感染的重组病毒疫苗的两个主要标准。理想的重组病毒疫苗不仅应该是复制缺陷型的并且能够引发广泛的保护性免疫反应，而且还应该编码一种安全机制，如果在宿主的相同细胞中遇到自然存在的野生型病毒，该机制可以抑制从头复制。单纯疱疹病毒 (HSV) 感染可导致严重的临床问题，甚至导致免疫缺陷或患有皮肤完整性疾病的个体死亡。美国大约 63% 的成年人感染 HSV。目前，没有有效的药物可以预防原发性 HSV 感染或降低复发率。因此，非常需要开发安全有效的HSV疫苗。我们最近生成了一种原型 HSV 重组病毒 CJ83193，它能够抑制自身复制以及野生型 HSV-1 和 HSV-2 的复制。基于 CJ83193 可作为小鼠 HSV-1 原发感染的预防性疫苗，其水平与野生型 HSV-1 相当，并且 CJ83193 作为减少复发感染的治疗性疫苗显示出巨大潜力，该研究计划的总体目标是进一步表征和开发一类新的 CJ83193 衍生 HSV 重组体，其安全性和 作为针对HSV感染的疫苗，其功效可以大大增强。本次拨款申请将采用和开发几种新颖的方法。具体目标 1 将重点开发 CJ83193-1ike HSV 重组体，该重组体具有更高的安全性和阻断野生型 HSV 病毒 DNA 复制的功效。这些 HSV 重组体作为针对小鼠模型中 HSV 感染的有效疫苗的潜力将在具体目标 2 中进行评估。鉴于 CJ83193 表达非常低水平的 HSV-1 主要抗原糖蛋白 gD，并且与其他众所周知的复制缺陷型 HSV 重组病毒疫苗一样，无法表达 gC（另一种 HSV 编码的主要糖蛋白）和 作为 CD4+ CTL 的主要目标，具体目标 3 的目标是通过基因开关增强源自 CJ83193 的重组 HSV 疫苗的功效，该基因开关可导致接种宿主中 gD 和/或 gC 的高水平表达。回想一下，B7 共刺激在抗 HSV 特异性细胞免疫和 T 细胞依赖性抗体反应的产生以及 HSV-1 感染未成熟 DC 导致 B7-1 和 B7-2 表达下调的过程中发挥着核心作用。具体目标4将重点研究HSV-1复制缺陷型疫苗病毒从头表达B7-1和B7-2对增强宿主针对HSV感染的免疫力的影响。