MOLECULAR BIOLOGY AND PATHOGENESIS OF MOUSE ADENOVIRUS

MAV-1为研究MAV-1的分子基础提供了一个模型系统 腺病毒致病机制，不能用更多的 广泛描述了人类腺病毒的特征。MAV-1引起急性 持续感染，以及病毒突变对 感染过程可以在自然动物宿主中进行研究。我们有 建立了MAV-1基因组的基本组织，确定了DNA 早期MAV-1两个关键基因的序列和转录图谱 区域1A(E1a)和早期区域3(E3)，并开发了一种方法 MAV-1基因组的体外定点突变。我们将利用 这些研究病毒宿主分子基础的进展 MAV-1基因E1a和E3的相互作用相应的人类 腺病毒基因产物与宿主细胞成分相互作用，并已被 被认为在腺病毒疾病中起着重要作用。人类 腺病毒E1a蛋白反式激活病毒和细胞基因，并形成 与细胞蛋白质的复合体，包括一种肿瘤抑制因子， 视网膜母细胞瘤蛋白(PRB)。这些活动有可能 对病毒致病机制的意义。在人腺病毒感染和 E3蛋白降低大鼠肝细胞癌I类抗原的表达 细胞表面的组织相容性复合体；这可能是一个因素 有助于腺病毒的持久化。我们将介绍具体的 MAV-1E1a和E3基因的突变，并检测它们对MAV-1E1a和E3基因的影响 病毒在细胞培养物和小鼠中的感染。早期的mRNA和蛋白质 合成、DNA复制、晚期蛋白质合成和相互作用 宿主细胞蛋白和病毒早期蛋白之间的关系将在 细胞培养。待研究的突变对小鼠的影响包括 致死率的变化，建立持续感染的能力， 变异病毒感染的组织特异性和进展，以及 宿主炎症反应。这些研究应该提供一个独特的 将动物病毒的分子生物学与 病毒致病的特定决定因素。

MAV- 1 provides a model system for studying the molecular basis of adenoviral pathogenesis, which cannot be pursued using the more extensively characterized human adenoviruses. MAV-1 causes acute persistent infections, and the effects of viral mutations on the infectious process can be studied in the natural animal host. We have established the basic organization of the MAV-1 genome, determined DNA sequences and transcription maps of two key early MAV- 1 genes, early region 1A (E1A) and early region 3 (E3), and developed an approach for in vitro site-specific mutagenesis of the MAV-1 genome. We will exploit these developments to study the molecular basis of virus-host interactions for MAV- 1 genes E1A and E3. The corresponding human adenovirus gene products interact with host cell components and have been postulated to have important roles in adenoviral disease. The human adenovirus E1A proteins transactivate viral and cellular genes, and form complexes with cellular proteins, including a tumor suppressor, the retinoblastoma protein (pRB). These activities have possible significance for viral pathogenesis. In human adenovirus infections an E3 protein reduces expression of class I antigens of the major histocompatibility complex on the cell surface; this may be a factor contributing to adenoviral persistence. We will introduce specific mutations into the MAV-1 E1A and E3 genes, and assay their effects on virus infections in both cell culture and mice. Early mRNA and protein synthesis, DNA replication, late protein synthesis, and interactions between host cell proteins and viral early proteins will be examined in cell culture. Effects of mutations to be studied in mice include variations in lethality, the ability to establish persistent infection, tissue specificity and progression of mutant virus infections, and the host inflammatory response. These studies should provide a unique opportunity to correlate the molecular biology of an animal virus with specific determinants responsible for viral pathogenesis.