EVALUATION OF ONCOGENIC FACTORS RELEVANT TO DEVELOPING SAFE HERPESVIRUS VACCINES

人类疱疹病毒6型(HHV-6)和人巨细胞病毒(HCMV)已被 被认为与某些人类恶性肿瘤有关。渐增 有证据表明HHV-6参与了多种淋巴增生性疾病 疾病和口腔癌。疱疹病毒的致癌潜力是 在拟议使用疱疹病毒活疫苗方面令人严重关切。 因此，我们研究了HHV-6和HHV-6的致癌潜力和性质。 以评估它们在人类癌症中的作用。 已经在基因组中识别并定位了两个转化域 将巨细胞病毒DNA克隆导入啮齿动物成纤维细胞和人 角质形成细胞，并检测细胞在裸鼠体内的肿瘤生长。一 的转化域被映射到一个79个氨基酸的开放 另一个为两个开放阅读框(ORF)，分别为270个氨基酸和 89-氨基酸多肽。限制对这些开放阅读框架的破坏 消化导致这些DNA在转化过程中不活跃，这表明 这些开放阅读框对于巨细胞病毒的转换功能是必不可少的。最直接的 已发现候选亚单位疫苗CMV的早期基因 不会致癌的。进一步研究黄曲霉的转化机制 由于技术支持减少，这些开放源码软件已停止使用。 使用类似的实验方法，已经得到了两个转换区域 在HHV-6基因组中鉴定。其中一个区域，称为ZVH14 (8，7KB)，已在各种霍奇金和非霍奇金中检测到 淋巴瘤和口腔癌。A型和B型毒株的基因组DNA 已经发现HHV-6的一部分在小鼠身上具有致瘤作用。要映射 转变领域，并理解转变的机制， 构建了ZVH14的缺失克隆，并对其进行研究。ZVH14 DNA和 可能编码115个氨基酸的亚克隆可以激活 与人或鼠Harvey ras连锁的报告基因的转录 推动者。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。

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. Further studies on the mechanism of transformation by these ORFs were discontinued because of decreased technical support. 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.