MOLECULAR BIOLOGY AND PATHOGENESIS OF MOUSE ADENOVIRUS

MAV- 1提供了一个模型系统，用于研究 腺病毒的发病机制，不能追求使用更多的 广泛表征的人腺病毒。 MAV-1引起急性 持续感染，以及病毒突变对 可以在自然动物宿主中研究感染过程。 我们有 建立了MAV-1基因组的基本结构， 两个关键的早期MAV- 1基因的序列和转录图谱， 区域1A（E1 A）和早期区域3（E3），并开发了一种方法， MAV-1基因组的体外位点特异性诱变。 我们将利用 研究病毒宿主的分子基础 MAV- 1基因E1 A和E3的相互作用。 相应的人 腺病毒基因产物与宿主细胞组分相互作用， 推测在腺病毒疾病中具有重要作用。 人类 腺病毒E1 A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物，包括肿瘤抑制因子， 视网膜母细胞瘤蛋白（pRB）。 这些活动有可能 病毒发病机制的重要性。 在人类腺病毒感染中， E3蛋白降低了主要免疫缺陷病毒I类抗原的表达。 细胞表面的组织相容性复合物;这可能是一个因素 有助于腺病毒的持久性。 我们将介绍具体的 MAV-1 E1 A和E3基因的突变，并测定它们对MAV-1 E1 A和E3基因的影响。 细胞培养物和小鼠中的病毒感染。 早期mRNA和蛋白质 合成，DNA复制，后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 在小鼠中研究的突变效应包括 致死率的变化，建立持续感染的能力， 突变病毒感染的组织特异性和进展， 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 负责病毒发病机制的特定决定因素。

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.