Upton C, Macen J L, Wishart D S, McFadden G
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Virology. 1990 Dec;179(2):618-31. doi: 10.1016/0042-6822(90)90129-f.
The leporipoxviruses Shope fibroma virus (SFV), the myxoma virus (MYX), and the SFV/MYX recombinant malignant rabbit fibroma virus (MRV) are closely related yet induce profoundly different diseases in the European rabbit. SFV, which produces a benign tumor at the site of inoculation, is cleared by the immune system after approximately 2 weeks whereas MYX and MRV induce a rapidly lethal systemic infection characterized by generalized suppression of host immune functions. DNA sequencing studies reveal that MRV and MYX possess homologous gene members of the T6/T8/T9 family originally described in the terminal inverted repeat (TIR) of SFV. We also describe a gene present in both MYX and MRV genomes, but which has apparently evolved in the SFV genome into a fragmented pseudogene that appears to contribute to the aggressive nature of MYX and MRV infections. Translation of this open reading frame, designated MYXOMA SERPIN 1 (SERP1), reveals a protein sequence with highly significant homology to the super-family of serine protease inhibitors (serpins) which also includes a number of other poxviral proteins. In the MYX genome the SERP1 gene lies entirely within the TIR sequences and is thus present as two copies, while in the MRV genome SERP1 is present in the unique sequences adjacent to the TIR boundary and hence is a single copy. The amino acid homology between the putative active site of SERP1 and those of other serpins predicts that the target enzyme will be different from the known catalog of serine antiprotease substrates. Deletion of this gene from MRV significantly attenuates the disease spectrum induced by the normally lethal virus. Although the MRV-S1 deletion construct (MRV with SERP1 gene deleted) grows in all tissue culture cells tested in a fashion identical to the MRV parent, the majority of rabbits infected with MRV-S1 are able to mount an effective immune response and totally recover from the virus infection to become resistant to subsequent challenge by MRV or MYX.
兔痘病毒属的肖普纤维瘤病毒（SFV）、黏液瘤病毒（MYX）以及SFV/MYX重组恶性兔纤维瘤病毒（MRV）密切相关，但在欧洲兔中引发的疾病却截然不同。SFV在接种部位产生良性肿瘤，约2周后被免疫系统清除，而MYX和MRV则引发迅速致命的全身感染，其特征为宿主免疫功能的普遍抑制。DNA测序研究表明，MRV和MYX拥有最初在SFV末端反向重复序列（TIR）中描述的T6/T8/T9家族的同源基因成员。我们还描述了一个同时存在于MYX和MRV基因组中的基因，但该基因在SFV基因组中显然已进化为一个片段化的假基因，这似乎有助于MYX和MRV感染的侵袭性。这个开放阅读框的翻译产物，命名为黏液瘤丝氨酸蛋白酶抑制剂1（SERP1），其蛋白质序列与丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂超家族）具有高度显著的同源性，该超家族还包括许多其他痘病毒蛋白。在MYX基因组中，SERP1基因完全位于TIR序列内，因此以两个拷贝的形式存在，而在MRV基因组中，SERP1存在于与TIR边界相邻的独特序列中，因此是单拷贝。SERP1推定活性位点与其他丝氨酸蛋白酶抑制剂的氨基酸同源性预测，其靶酶将不同于已知的丝氨酸抗蛋白酶底物目录。从MRV中删除该基因可显著减弱由这种通常致命的病毒诱导的疾病谱。尽管MRV-S1缺失构建体（删除了SERP1基因的MRV）在所有测试的组织培养细胞中生长方式与MRV亲本相同，但大多数感染MRV-S1的兔子能够产生有效的免疫反应，并从病毒感染中完全康复，从而对随后的MRV或MYX攻击产生抗性。
