Dai H Y, Troseth G I, Gunleksrud M, Bruland T, Solberg L A, Aarset H, Kristiansen L I, Dalen A
Unigen Center for Molecular Biology, Norwegian University of Science and Technology, Trondheim.
J Virol. 1998 Feb;72(2):1244-51. doi: 10.1128/JVI.72.2.1244-1251.1998.
An immunosuppressive variant of Friend murine leukemia virus (F-MuLV), FIS-2, induces suppression of the primary antibody response against sheep erythrocytes (SRBC) in adult NMRI mice more efficiently than the prototype F-MuLV clone 57 (cl.57). It is, however, less potent than F-MuLV cl.57 in inducing erythroleukemia upon inoculation into newborn NMRI mice. Nucleotide sequence analysis shows a high degree of homology between the two viruses. Single point mutations are scattered over both the gag and the env encoding regions. The most notable mutations are the deletion of one direct repeat and a few single point mutations occurring in the binding sites for cellular transcriptional factors in the FIS-2 long terminal repeat region (LTR). To define the genetic determinants responsible for the pathogenic properties of FIS-2, we constructed six chimeras between FIS-2 and F-MuLV cl.57. Adult mice were infected with the chimeras, and their primary antibody responses against SRBC were investigated. The results showed that the fragment encompassing the FIS-2 env encoding region SU is responsible for the increased immunosuppressive activity in adult mice. A leukemogenicity assay was also performed by infecting newborn mice with the chimeras. Consistent with the previous studies, it showed that the deletion of one direct repeat in the FIS-2 LTR is responsible for the long latent period of erythroleukemia induced by FIS-2 in newborn-inoculated mice. However, studies of cell type-specific transcriptional activities of FIS-2 and F-MuLV cl.57 LTRs using LTR-chloramphenicol acetyltransferase constructs showed that the deletion of one direct repeat does not reduce the transcriptional activity of the FIS-2 LTR. The activity is either comparable to or higher than the transcriptional activity of the F-MuLV cl.57 LTR in the different cell lines that we used, even in an erythroleukemia cell line. It seems that the high transcriptional strength of the FIS-2 LTR is not sufficient to give FIS-2 a high leukemogenic effect. This suggestion is inconsistent with the previous suggestion that the transcriptional strength of an LTR in a given cell type is correlated with the leukemogenic potential in the corresponding tissue. In other words, these data indicate that the direct repeats in the F-MuLV LTR may play other roles besides transcriptional enhancer in the leukemogenesis of F-MuLV.
弗瑞德氏鼠白血病病毒（F-MuLV）的一种免疫抑制变体FIS-2，在成年NMRI小鼠中，比原型F-MuLV克隆57（cl.57）更有效地抑制针对绵羊红细胞（SRBC）的初次抗体反应。然而，在接种新生NMRI小鼠后，它诱发红白血病的能力比F-MuLV cl.57弱。核苷酸序列分析表明这两种病毒之间有高度的同源性。单点突变散布在gag和env编码区域。最显著的突变是FIS-2长末端重复序列（LTR）中一个直接重复序列的缺失以及细胞转录因子结合位点出现的一些单点突变。为了确定导致FIS-2致病特性的遗传决定因素，我们构建了FIS-2和F-MuLV cl.57之间的六个嵌合体。用这些嵌合体感染成年小鼠，并研究它们针对SRBC的初次抗体反应。结果表明，包含FIS-2 env编码区域SU的片段导致成年小鼠免疫抑制活性增加。还通过用嵌合体感染新生小鼠进行了致白血病性测定。与先前的研究一致，结果表明FIS-2 LTR中一个直接重复序列的缺失导致在新生接种小鼠中FIS-2诱发的红白血病潜伏期延长。然而，使用LTR-氯霉素乙酰转移酶构建体对FIS-2和F-MuLV cl.57 LTR的细胞类型特异性转录活性进行的研究表明，一个直接重复序列的缺失并不会降低FIS-2 LTR的转录活性。在我们使用的不同细胞系中，甚至在一个红白血病细胞系中，该活性与F-MuLV cl.57 LTR的转录活性相当或更高。似乎FIS-2 LTR的高转录强度不足以赋予FIS-2高致白血病效应。这一观点与先前的观点不一致，即给定细胞类型中LTR的转录强度与相应组织中的致白血病潜力相关。换句话说，这些数据表明F-MuLV LTR中的直接重复序列在F-MuLV白血病发生过程中除了转录增强子作用外可能还发挥其他作用。
