CELLULAR HOMOLOGS OF HERPESVIRUS GENES

1)疱疹病毒引起潜伏感染，持续终生 这些病毒已经发展出一种机制来中和 宿主进行防御，以便让病毒持续存在。使用复杂的 计算机程序我们正在识别疱疹病毒基因可能有 细胞同源物。这些基因在不同的系统中表达 为了确定这些基因如何与宿主细胞蛋白相互作用， 包括免疫系统，以影响感染的过程- 提顿。识别这些基因可能有助于确定新的靶点 抗病毒治疗或对调节免疫系统的新见解。2) 爱泼斯坦-巴尔病毒(EBV)编码一种II型膜蛋白BZLF2， 与C型凝集素家族成员同源。在协作中 在免疫公司的帮助下，我们构建了一种可溶性的融合蛋白 含有与人免疫球蛋白Fc结构域连接的胞外结构域 BZLF2.BZLF2的胞外区与人结合 MHCⅡ类人类白细胞抗原-DRβ链。人类白细胞抗原-DR的定点突变 Beta链表明识别需要Beta1结构域 BZLF2的胞外区。由于此域参与了 形成了多肽结合口袋，这些结果表明BZLF2 可能会干扰II类定向抗原提呈。核聚变 含有BZLF2抑制抗原胞外区的蛋白 抗原特异性细胞毒T淋巴细胞的呈递和产生 在混合淋巴细胞培养中。目前的研究方向是 在EB病毒中灭活BZLF2基因以确定该蛋白的作用 在细胞培养和动物模型中病毒的生长过程中。 3)VZV ORF13编码病毒胸苷 合成酶。这种蛋白质与人类有68%的氨基酸同源性。 胸苷合成酶。我们已经在Oka疫苗中构建了一个突变体 不能表达病毒胸苷合成酶的VZV菌株 在基因中插入终止密码子。我们计划给晚点的豚鼠接种疫苗 用VZV突变体来确定病毒胸苷合成酶 对感染病毒或传播能力很重要 中枢神经系统，并保持潜伏感染。4) 已知的哺乳动物蛋白的其他疱疹病毒同源物已经被 已确认身份。有希望的候选人将在适当的系统中进行研究 与免疫公司的M.Spriggs合作。

1) Herpesviruses cause latent infections that persist for the lifetime of the host and these viruses have developed mechanisms to counteract host defenses so as to allow the virus to persist. Using sophisticated computer programs we are identi-fying herpesvirus genes that may have cellular homologs. These genes are being expressed in various systems to determine how the genes may interact with host cell proteins, including those of the immune system, to influence the course of infec- tion. Identification of these genes may help define new targets for antiviral therapy or new insights into modulating the immune system. 2) Epstein-Barr virus (EBV) encodes a type II membrane protein, BZLF2, that is homologous to members of the C-type lectin family. In collaboration with Immunex Corporation, we have constructed a soluble fusion protein containing the human IgG Fc domain linked to the extracellular domain of BZLF2. The extracellular domain of BZLF2 was found to bind to the human MHC class II HLA-DR beta chain. Site directed mutagenesis of the HLA-DR beta chain indicated that the beta1 domain was required for recognition of the extracellular domain of BZLF2. Since this domain participates in forming the peptide binding pocket, these results suggested that BZLF2 may interfere with class II directed antigen presentation. The fusion protein containing the extracellular domain of BZLF2 inhibited antigen presentation and generation of antigen-specific cytotoxic T lymphocytes in mixed lymphocyte cultures. Current studies are directed toward inactivating the BZLF2 gene in EBV to determine the role of the protein during growth of the virus both in cell culture and in an animal model. 3) Vari-cella-zoster virus (VZV) ORF13 encodes the viral thymidylate synthetase. This protein has 68% amino acid identity to the human thymidylate synthetase. We have constructed a mutant in the Oka vaccine strain of VZV that cannot express the viral thymidylate synthetase by inserting stop codons into the gene. We plan to inocu-late guinea pigs with the VZV mutant to determine whether viral thymidylate synthe-tase is important for infection with the virus or for the ability to spread to the central nervous system and maintain latent infection. 4) Additional herpesvirus homologs of known mammalian proteins have been identified. Promising candidates will be studied in appropriate systems in collaboration with M. Spriggs at Immunex Corporation.