A Systematic Analysis of Host Factors Reveals a Med23-Interferon-? Regulatory Axis against Herpes Simplex Virus Type 1 Replication

Griffiths, Samantha J.; Koegl, Manfred; Boutell, Chris; Zenner, Helen L.; Crump, Colin M.; Pica, Francesca; Gonzalez, Orland; Friedel, Caroline C.; Barry, Gerald; Martin, Kim; Craigon, Marie H.; Chen, Rui; Kaza, Lakshmi N.; Fossum, Even; Fazakerley, John K.; Efstathiou, Stacey; Volpi, Antonio; Zimmer, Ralf; Ghazal, Peter; Haas, Jürgen

Investigations into the mechanism of action revealed Med23 inhibits HSV-1 replication by preferentially inducing a type III interferon response (IFN-l) at the mRNA and protein level. This induction was mediated via a direct interaction with the transcription factor IRF7, which resulted in a synergistic increase in IFN-l expression. Med23 was unable, however, to further enhance IRF7-induced levels of IFN-b, suggesting an additional level of complexity to the regulation of interferon signalling. Interestingly, the inhibitory effect of Med23 was specific to HSV-1, with replication of a range of other viruses including Vaccinia virus and Semliki Forest Virus being unaffected by Med23 depletion. As Vaccinia virus is resistant to IFN-l anti-viral activity [62] , this observation further highlights the importance of IFN-l, as opposed to IFN-b, in the anti-viral effect of Med23. The R617Q mutation in Med23 (R611Q in Med23 transcript variant 1, used here) was unable to enhance IRF7-induced IFN-l expression. This mutation causes hereditary dementia [63] , and the failure to induce IFN-l and thereby control HSV-1 in the brain may be a potential cofactor for the development of dementia, similar to Alzheimer's disease [64] . There is mounting evidence for a role of the IFN-l family in the regulation of virus pathogenesis [45] , particularly in the case of Hepatitis C infection where a polymorphism in the promoter region of IFN-l3 (IL-28B; polymorphism rs12979860), which correlates with plasma levels of IFN-l3 [50] , is associated with disease and treatment outcome [49] . Individuals with recurrent HSV-1 reactivation have been shown to be deficient in IFN-l expression [51] , and here we found the similar association between the IFN-l3 promoter polymorphism and ethnically Italian patients suffering recurrent and severe reactivations of HSV-1-related oral herpes outbreaks, albeit with a small sample group (n = 58). Furthermore, sporadic mutations and genetic polymorphisms in innate immune receptor and signalling molecules that lead to the induction of type I and III IFNs have also been shown to be associated with Herpes Encephalitis [65] , as well as oral and genital Herpes [66, 67] .