Self-limiting, and Dominant-negative HSV Recombinants

自限性和显性阴性 HSV 重组体

• 批准号: 6989050
• 负责人: FENG YAO
• 金额: $ 32.36万
• 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989050
• 关键词: DNA replication; Herpesviridae vaccine; biotechnology; enzyme linked immunosorbent assay; flow cytometry; glycoproteins; herpes simplex virus 1; laboratory mouse; vaccine development; vaccine evaluation; vector vaccine; virus genetics; virus protein; virus replication

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（由申请方提供）：安全性和引发有效宿主免疫应答的效率是开发抗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，能够引发广泛的保护性免疫应答，而且还应该编码一种安全机制，如果在宿主的相同细胞内遇到，该机制可以抑制天然存在的野生型病毒的从头复制。单纯疱疹病毒（HSV）感染可导致免疫缺陷或患有皮肤完整性疾病的个体出现重大临床问题，甚至死亡。在美国，大约63%的成年人感染了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。我们最近产生了一种原型HSV重组病毒，CJ 83193，它能够抑制其自身的复制以及野生型HSV-1和HSV-2的复制。基于CJ 83193可作为预防性疫苗在小鼠中以与野生型HSV-1相当的水平对抗HSV-1初次感染，并且CJ 83193已显示出作为治疗性疫苗减少复发感染的巨大潜力，这项研究计划的总体目标是进一步表征和开发一种新的CJ 83193-衍生的HSV重组体，其作为抗HSV感染的疫苗的安全性和效力可以大大提高。在这项资助申请中，将采用和开发几种新的方法。具体目标1将集中于开发具有增加的安全性特征和阻断野生型HSV病毒DNA复制的有效性的CJ 83193样HSV重组体。这些HSV重组体作为小鼠模型中抗HSV感染的有效疫苗的潜力将在特定目标2中进行评价。鉴于CJ 83193表达非常低水平的HSV-1主要抗原糖蛋白gD，并且像其它公知的复制缺陷型HSV重组病毒疫苗一样，不能表达gC，另一种HSV编码的主要糖蛋白和CD 4 + CTL的主要靶标，具体目标3的目标是增强具有基因开关的CJ 83193衍生的重组HSV疫苗的效力，所述基因开关可导致gD和/或gD的高水平表达。或gC在接种疫苗的宿主中。回想一下，B7共刺激在产生抗HSV特异性细胞免疫和T细胞依赖性抗体应答以及HSV-1感染未成熟DC导致B7-1和B7-2表达下调中起着核心作用。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对增强宿主抗HSV感染免疫力的影响。