Self-limiting, and Dominant-negative HSV Recombinants

自限性和显性阴性 HSV 重组体

• 批准号: 6828240
• 负责人: FENG YAO
• 金额: $ 33.19万
• 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/6828240
• 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(由申请人提供)：安全和高效地诱导有效的宿主免疫反应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的，能够引起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内遇到自然产生的野生型病毒，可以抑制从头开始复制。单纯疱疹病毒(HSV)感染会导致严重的临床问题，甚至会导致免疫缺陷或皮肤完整性障碍的人死亡。在美国，大约63%的成年人感染了HSV。目前，还没有有效的药物可以预防原发HSV感染或降低复发的发生率。因此，开发一种安全有效的单纯疱疹病毒疫苗是非常必要的。我们最近获得了一个HSV重组病毒原型CJ83193，它能够抑制自身以及野生型HSV-1和HSV-2的复制。鉴于CJ83193可以作为预防小鼠初次感染HSV-1的疫苗，其水平与野生型HSV-1相当，而且CJ83193作为治疗性疫苗在减少复发感染方面显示出巨大的潜力，本研究的总体目标是进一步鉴定和开发一类新的来源于CJ83193的HSV重组体，其作为HSV感染疫苗的安全性和有效性可以大大提高。在这项赠款申请中将采用和开发几种新的方法。具体目标1将重点开发具有更高安全性和阻断野生型单纯疱疹病毒DNA复制效果的CJ83193-1ike HSV重组体。鉴于CJ83193表达的HSV-1主要抗原糖蛋白gD水平很低，并且像其他众所周知的复制缺陷HSV重组病毒疫苗一样，不能表达gC，GC是另一种HSV编码的主要糖蛋白，也是CD4+CTL的主要靶点，特定目标3的目标是通过基因开关提高CJ83193衍生的重组HSV疫苗的效力，该基因开关可能导致gD和/或gC在接种宿主中高水平表达。回想一下，B7共刺激在产生抗HSV特异性细胞免疫和T细胞依赖的抗体反应以及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核心作用。具体目的4将重点研究HSV-1复制缺陷疫苗病毒从头表达B7-1和B7-2对增强宿主对HSV感染免疫的影响。