CELLULAR HOMOLOGS OF HERPESVIRUS GENES

1)疱疹病毒引起的潜伏感染持续一生 而这些病毒已经发展出了一种机制， 宿主防御系统，以便让病毒持续存在。 使用复杂 我们正在通过计算机程序识别疱疹病毒基因， 细胞同源物 这些基因在不同的系统中表达 为了确定基因如何与宿主细胞蛋白质相互作用， 包括免疫系统，以影响感染的过程， 是的。 这些基因的鉴定可能有助于确定新的靶点， 抗病毒治疗或调节免疫系统的新见解。（二） EB病毒（EBV）编码II型膜蛋白BZLF 2， 与C型凝集素家族成员同源。 合作 与Immunex公司合作， 构建了可溶性融合蛋白 含有连接至人IgG Fc结构域的胞外结构域的人IgG Fc结构域 BZLF 2. 发现BZLF 2的细胞外结构域与人BZLF 2结合。 MHC II类HLA-DR β链。 HLA-DR的定点突变 β链表明β 1结构域是识别所必需的 BZLF 2的胞外区。 由于此域参与 形成肽结合口袋，这些结果表明BZLF 2 可能干扰II类定向抗原呈递。 融合 含有BZLF 2抑制抗原胞外区的蛋白质 抗原特异性细胞毒性T淋巴细胞的呈递和产生 在混合淋巴细胞培养中。 目前的研究是针对 灭活EBV中的BZLF 2基因以确定蛋白质的作用 在细胞培养物和动物模型中的病毒生长期间。 3)水痘带状疱疹病毒（VZV）ORF 13编码病毒胸苷酸 合成酶 该蛋白质与人的氨基酸同源性为68%。 胸苷酸合成酶 我们在奥卡疫苗中制造了一个突变体 不能表达病毒胸苷酸合成酶的VZV菌株， 在基因中插入终止密码子。 我们计划给豚鼠注射疫苗 用VZV突变体来确定病毒胸苷酸合成酶 对病毒的感染或传播能力很重要 中枢神经系统并保持潜伏感染四、 已知哺乳动物蛋白质的其它疱疹病毒同源物已被发现。 鉴定 有前途的候选人将在适当的系统中进行研究 与M. Immunex Corporation的Spriggs。

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.