EVALUATION OF ONCOGENIC FACTORS RELEVANT TO DEVELOPING SAFE HERPESVIRUS VACCINES

与开发安全疱疹病毒疫苗相关的致癌因素的评估

• 批准号: 2568935
• 负责人: A RAZZAQUE
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2568935
• 关键词: Herpesviridae vaccine; athymic mouse; carcinogen testing; cytomegalovirus; drug design /synthesis /production; drug quality /standard; human herpesvirus 6; human tissue; lymphoma; molecular oncology; mouth neoplasms; oncogenes; open reading frames; transforming virus; vaccine development; viral carcinogenesis; virus genetics; virus related neoplasm /cancer

Human herpesvirus-6 (HHV-6) and human cytomegalovirus (HCMV) have been suggested to be associated with some human malignancies. Increasing evidences suggest the involvement of HHV-6 in various lymphoproliferative disorders and oral carcinomas. Oncogenic potential of herpesviruses is of significant concern in the proposed use of live herpesvirus vaccines. Therefore, we studied the oncogenic potential and properties of HHV-6 and HCMV to evaluate their role in human cancers. Two transforming domains have been identified and mapped in the genome of CMV by introducing CMV DNA clones into rodent fibroblasts and human keratinocytes and assaying the cells for tumor growth in nude mice. One of the transforming domains has been mapped to a 79-amino acid open reading frame (ORF) and the other to two ORFs of 270-amino acid and 89-amino-acid peptides. Disruption of these ORFs by restriction digestion caused these DNAs inactive in transformation suggesting that these ORFs are essential for transforming function of CMV. The immediate early gene of CMV, a candidate subunit vaccine, has been found non-tumorigenic. Using a similar experimental approach, two transforming regions have been identified in the genome of HHV-6. One of the regions, called ZVH14 (8,7 KB), has been detected in various Hodgkin's and non-Hodgkin's lymphomas and oral carcinomas. Genomic DNAs of both A and B type strains of HHV-6 have been found to be tumorigenic in mice. To map the transforming domain and to understand the mechanism of transformation, deletion clones from ZVH14 were generated and studied. The ZVH14 DNA and a subclone potentially encoding a 115 amino acid-protein could activate transcription of a reporter gene linked to a human or mouse Harvey ras promoters. These data suggest that HHV-6 transforming genes may act through transcriptional activation of some cellular genes or oncogenes.

人类疱疹病毒-6（HHV-6）和人类巨细胞病毒（HCMV）已经被广泛应用于人类免疫系统。 提示与某些人类恶性肿瘤有关。 增加 有证据表明HHV-6参与了各种淋巴组织增生性疾病， 疾病和口腔癌。 疱疹病毒的致癌潜力是 在建议使用疱疹病毒活疫苗时引起严重关注。 因此，我们研究了HHV-6的致癌潜力和特性， HCMV，以评估其在人类癌症中的作用。 两个变换域 通过引入CMV， DNA克隆入啮齿动物成纤维细胞和人角质形成细胞并测定 用于裸鼠肿瘤生长的细胞。 其中一个转变 结构域已被定位到79个氨基酸的开放阅读框（ORF）， 另一个编码270个氨基酸和89个氨基酸的多肽。 通过限制性消化破坏这些ORF， 在转化中无活性，这表明这些ORF对于 CMV的转化功能。 CMV即早基因a 候选亚单位疫苗，已发现非致瘤性。 使用 类似的实验方法，两个转换区域已被 在HHV-6的基因组中鉴定。 其中一个区域，称为ZVH 14（8，7 KB），已在各种霍奇金和非霍奇金淋巴瘤中检测到 和口腔癌。 人疱疹病毒6型A、B型毒株基因组DNA的比较 在小鼠体内发现有致瘤性。 映射变换 结构域，并了解转化，缺失克隆的机制 从ZVH 14产生和研究。 ZVH 14 DNA和亚克隆 一种可能编码115个氨基酸的蛋白质可以激活 与人或小鼠Harvey ras基因连锁的报告基因的转录 发起人。 这些数据表明，HHV-6转化基因可能起作用， 通过转录激活某些细胞基因或癌基因。