A glucocorticoid response element in the LTR U3 region of Friend murine leukaemia virus variant FIS-2 enhances virus production in vitro and is a major determinant for sex differences in susceptibility to FIS-2 infection in vivo
A glucocorticoid response element in the LTR U3 region of Friend murine leukaemia virus variant FIS-2 enhances virus production in vitro and is a major determinant for sex differences in susceptibility to FIS-2 infection in vivo
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DOI：
10.1099/vir.0.18625-0
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发表时间：
2003-04-01
影响因子：
3.8
通讯作者：
Dalen, A
中科院分区：
文献类型：
--
作者：
Bruland, T;Lavik, LAS;Dalen, A
Friend鼠白血病病毒变体FIS-2 LTR的核苷酸序列与密切相关的Friend鼠白血病病毒（F-MuLV）LTR具有高度同一性，除了在U3区缺失一个同向重复序列、几个点突变和产生糖皮质激素反应元件（GRE）。GRE可以介导糖皮质激素、矿物质皮质激素、孕酮和雄激素的基因诱导，并且已经显示在LTR内掺入GRE可以增加逆转录病毒增强子的转录活性。我们以前曾报道过，与雌性小鼠相比，雄性小鼠感染含有FIS-2 LTR的病毒时，早期病毒复制增加，并提出GRE可能有助于这种性别差异。在本研究中，我们在GRE中引入了一个单点突变，并在NIH 3 T3细胞和年轻的成年雄性和雌性NMRI小鼠中进行了比较研究。我们发现，从感染野生型FIS-2的NIH 3 T3细胞比从感染FIS-2 GRE突变体的细胞产生更多的病毒，并且糖皮质激素进一步增强了这种差异。糖皮质激素拮抗剂RU 486以剂量依赖性方式抑制病毒产生。在雄性和雌性小鼠中，野生型FIS-2比FIS-2 GRE突变体传播得更快。感染FIS-2 GRE突变体的雄性和雌性小鼠之间的传播率没有显著差异。因此，FIS-2 LTR中的GRE是FIS-2感染易感性存在显著性别差异的决定因素之一。
The nucleotide sequence of the Friend murine leukaemia virus variant FIS-2 LTR has high identity with the closely related Friend murine leukaemia virus (F-MuLV) LTR, except for the deletion of one direct repeat, a few point mutations and the generation of a glucocorticoid response element (GRE) in the U3 region. The GRE can mediate gene induction by glucocorticoids, mineral corticoids, progesterone and androgens, and it has been shown that incorporation of a GRE(s) within the LTR can increase the transcriptional activity of retroviral enhancers. We have previously reported an increased early virus replication in male mice compared with female mice when infected with a virus containing the FIS-2 LTR and have proposed that the GRE might contribute to this sex difference. In the present study, we introduced a single point mutation in the GRE and performed comparative studies in NIH 3T3 cells and in young adult male and female NMRI mice. We found that significantly more virus was produced from NIH 3T3 cells infected with wt FIS-2 than from cells infected with the FIS-2 GRE mutant and that this difference was further augmented by glucocorticoids. The glucocorticoid antagonist RU486 inhibited virus production in a dose-dependent manner. The wt FIS-2 disseminated significantly faster than the FIS-2 GRE mutant in both male and female mice. There was no significant difference in the dissemination rate between male and female mice infected with the FIS-2 GRE mutant. Hence, the GRE in the FIS-2 LTR is one determinant of the significant sex difference in susceptibility to FIS-2 infection.