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

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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.