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。两个变换域 已通过引入CMV在CMV基因组中进行了鉴定和定位 鼠成纤维细胞和人角质形成细胞的DNA克隆及检测 裸鼠体内肿瘤生长的细胞。转型中的一个 结构域已被映射到一个79个氨基酸的开放阅读框架(ORF)和 另一种为两个ORF270-氨基酸和-氨基酸多肽。 限制性内切酶对这些ORF的破坏导致了这些DNA 在转换中不活跃表明这些ORF对于 CMV的变换函数。CMV的即刻早期基因 候选亚单位疫苗，已被发现不会致癌。使用 类似的实验方法，已经有两个转化区域 在HHV-6基因组中鉴定。其中一个区域，称为ZVH14(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。HHV-6A、B型毒株的基因组DNA 已被发现在小鼠身上具有致癌作用。绘制转型地图 并了解转化、删除克隆的机制 从ZVH14中产生并研究了该基因。ZVH14DNA及其亚克隆 潜在编码115个氨基酸的蛋白质可以激活 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. 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.