Viral factors involved in Marek's disease virus (MDV) genome integration

一些疱疹病毒，包括鸡的高致癌性马立克病病毒（MDV），可以将其遗传物质整合到宿主端粒中，从而确保病毒基因组在潜伏期的维持1,2。MDV和其他几种疱疹病毒在其线性基因组的两端都含有端粒重复序列（TMRs） 3,4。MDV在两端指定一个可变长度的长TMR （mTMR）和一个只有6个重复的短TMR （sTMR）。我们最近证明mTMR区域对于MDV基因组整合到宿主端粒至关重要，并且整合对于有效的淋巴瘤发生和潜伏期的再激活至关重要。然而，sTMR区域在MDV复制和整合中的作用仍不清楚。MDV还编码两种蛋白，pUL12和ICP8，这可能是病毒重组机制的一部分，这一解释得到了单纯疱疹病毒pUL12和ICP8在体外促进重组的事实的支持。在这里，我们将验证MDV基因组末端的sTMR区域和MDV编码的pUL12和ICP8促进病毒基因组整合到宿主端粒的假设。我们将通过两个具体目标来检验我们的假设：1)确定sTMR区域在MDV复制、整合和疾病发展中的作用。2)测试假设的MDV pUL12/ICP8重组酶复合体是否有助于病毒基因组整合，以及整合是否需要病毒和/或细胞DNA复制。

Some herpesviruses, including the highly oncogenic Marek’s disease virus (MDV) of chickens, can integrate their genetic material into host telomeres, which ensures viral genome maintenance during latency1, 2. MDV and several other herpesviruses harbor telomeric repeats (TMRs) at either end of their linear genomes3, 4. MDV specifies at both termini a long TMR (mTMR) with variable length and a short TMR (sTMR) with only 6 repeats . We recently demonstrated that the mTMR region is essential for MDV genome integration into host telomeres and that integration is critical for efficient lymphomagenesis and reactivation from latency. However, the role of the sTMR region in MDV replication and integration has remained unclear. MDV also encodes two proteins, pUL12 and ICP8, that may be part of the viral recombination machinery, an interpretation supported by the fact that pUL12 and ICP8 of herpes simplex virus facilitate recombination in vitro. Here, we will test the hypothesis that the sTMR region at the MDV genomic termini and the MDV encoded pUL12 and ICP8 facilitate integration of the virus genome into host telomeres. We will test our hypothesis by two specific aims: 1) To determine the role of the sTMR region in MDV replication, integration, and disease development. 2) To test if the putative MDV pUL12/ICP8 recombinase complex facilitates virus genome integration and if integration requires viral and/or cellular DNA replication.