A Shutoff and Exonuclease Mutant of Murine Gammaherpesvirus-68 Yields Infectious Virus and Causes RNA loss in Type I Interferon Receptor Knock-Out cells

Significant loss of RNA followed by severely reduced cellular protein pool, a phenomenon termed host shutoff, is associated with a number of lytic virus infections and is a critical player in virus pathogenesis. Until recently, viral DNA exonucleases were associated only with processing of viral genomic DNA and encapsidation. However, recent observations have identified a combined host shutoff and exonuclease function for the highly conserved viral exonucleases in γ- herpesviruses which include Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus and the murine model murine gammaherpesvirus-68. In this study, we show that although ablation of the MHV-68 exonuclease ORF37 caused a restrictive phenotype in interferon-α/β receptor-positive cells, lack of ORF37 was tolerated in cells lacking the interferon- α /β receptor: the ORF37 deletant virus was capable of forming infectious particles and caused loss of RNA in interferon-α/β receptor knockout cells. Moreover, ORF37 deletant virus was able to establish lytic infection in lungs of mice lacking the interferon-α/β receptor. These observations provide further evidence that this family of viral nucleases play a key role in providing a window of opportunity for virus growth by overcoming type I IFN-dependent responses by host shutoff of cellular transcripts.