Viral control of vTR expression is critical for efficient formation and dissemination of lymphoma induced by Marek's disease virus (MDV)
Viral control of vTR expression is critical for efficient formation and dissemination of lymphoma induced by Marek's disease virus (MDV)
复制标题
DOI：
10.1051/vetres/2010026
复制
发表时间：
2010-09-01
影响因子：
4.4
通讯作者：
Osterrieder, Nikolaus
中科院分区：
文献类型：
--
作者：
Chbab, Najat;Egerer, Annemarie;Osterrieder, Nikolaus
马立克氏病病毒（MDV）是一种α疱疹病毒，可引起鸡的致命性T细胞淋巴瘤。MDV的独特之处在于其基因组中含有两个拷贝的病毒端粒酶RNA亚基（vTR），与鸡的直系同源物chTR具有88%的序列同一性。最小的端粒酶核糖核蛋白复合物由具有逆转录酶活性（TERT）和TR的蛋白质亚基组成。在生理上，该复合物补偿有丝分裂期间发生的进行性端粒缩短，并参与细胞永生化的过程。以前的研究表明MDV vTR在肿瘤发生过程中起辅助作用。病毒和鸡TR启动子的体外比较分析表明，在禽类细胞中，vTR启动子（PvTR）的效率比chTR启动子（PchTR）高3倍，并且PvTR的较强转录活性主要来自位于vTR基因转录起始位点下游两个核苷酸的E盒。为了检验PvTR是vTR表达所需的假设，因此，有效的肿瘤形成，我们产生了一种重组病毒，vPchTR（+/+），其中vTR启动子被chTR的启动子取代。在体内，vPchTR（+/+）的生长与亲本病毒的生长不可区分;然而，与亲本病毒诱导的那些相比，肿瘤诱导减少> 50%，并且淋巴瘤更小且更少扩散。我们的结论是，PvTR是不需要在体内裂解复制，但有效的转录vTR是必不可少的，从而有效的MDV淋巴瘤形成的关键。
Marek's disease virus (MDV) is an alphaherpesvirus that causes lethal T-cell lymphomas in chickens. MDV is unique in that it harbors two copies of a viral telomerase RNA subunit (vTR) in its genome exhibiting 88% sequence identity to the chicken orthologue, chTR. The minimal telomerase ribonucleoprotein complex consists of a protein subunit with reverse transcriptase activity (TERT) and TR. Physiologically, the complex compensates for the progressive telomere shortening that occurs during mitosis and is involved in the process of cellular immortalization. Previous studies showed that MDV vTR performes an auxiliary function during oncogenesis. Comparative in vitro analysis of the viral and chicken TR promoters revealed that the vTR promoter (PvTR) was up to 3-fold more efficient than the chTR promoter (PchTR) in avian cells and that the stronger transcriptional activity of PvTR resulted largely from an E-box located two nucleotides downstream of the transcriptional start site of the vTR gene. To test the hypothesis that PvTR is required for vTR expression and, hence, efficient tumor formation, we generated a recombinant virus, vPchTR(+/+), in which the vTR promoter was replaced by that of chTR. In vivo, growth of vPchTR(+/+) was indistinguishable from that of parental virus; however, tumor induction was reduced by > 50% and lymphomas were smaller and less disseminated when compared to those induced by parental virus. We concluded that PvTR is not required for lytic replication in vivo but is essential for efficient transcription of vTR and thereby critical for efficient MDV lymphoma formation.