Herpesviruses have evolved sophisticated ways to subvert the immune system during millions of years of coevolution with their respective hosts. The nine human members of the herpesvirus family include important human pathogens like Herpes-simplex viruses-1 and -2 (HSV-1 and HSV-2), Varicella-Zoster Virus (VZV), Human Cytomegalovirus (HCMV), Human Herpesviruses-6A, -6B and -7 and the tumor viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV). A hallmark of herpesvirus infections is the establishment of lifelong latency, for example about 3.7 billion people alone are infected with HSV-1 worldwide, and even more by HHV-6, -7 and EBV.
The goal of this project was the identification of novel restriction or host factors of herpesviruses that are involved or interfere with initiation of herpesviral gene expression and replication. Therefore a new method called HyCCAPP should be developed in order to discover new factors that associate with the viral genome upon nuclear entry. Although the initially proposed approach was not successful, we used alternative methods, namely CRISPRainbow- and EdC-labelling of viral genomes that allowed us to identify SMCHD1 as a novel restriction factor for herpesviruses that is associated with viral genomes. SMCHD1 is an important human protein, and mutations in SMCHD1 have been shown to be the cause of two genetic diseases, Facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphtalmia syndrome (BAMS). We characterized SMCHD1 in detail as antiviral protein and could even show viral antagonism of SMCHD1-mediated restriction by a protein of KSHV, further corroborating the importance of SMCHD1 in antiviral immunity. We hope that our discovery of a new antiviral restriction factor may help to understand the pathogenicity of herpesviral disease and contribute to the development of new anti-herpesviral drugs in the future.
