A Novel Immune Evasion Mechanism by Human Alphaherpesviruses

Abstract

Type I interferon induced MxA has antiviral activity against RNA viruses. Here we demonstrate a previously unrecognized MxA isoform induced by herpes simplex virus‐1 (HSV‐1) in human fibroblasts. Transcript encoding MxA splice variant has a deletion in Exons 14–16 which encode a central interactive domain associated with recognition of viral nucleocapsids and is predicted to encode a novel peptide sequence at the C‐terminal region as compared with IFN ‐induced MxA prototype. Polyclonal antiserum raised in rabbit against C‐terminal half of MxA splice variant demonstrated that HSV‐1 induced variant MxA undergoes nuclear translocation associated with viral replication compartment. Infection of variant MxA‐overexpressing fibroblasts with HSV‐1 resulted in the enhancement of viral yields but the yields were decreased in MxA‐knockdown cell by siRNA, suggesting that HSV‐1 induced MxA splice variant enhances viral replication. Both IFN‐ α and HSV‐1 are able to activate the promoter of MxA in luciferase reporter assay; however, only the MxA variant is translated in virus‐infected cells. Thus, differential expression of MxA controlled by IFN‐α or HSV‐1 could result in the increase of host resistance or favoring viral replication, depending on stimulating event. In summary, modulation of cellular mRNA could be a novel mechanism for human alphaherpesviruses to avoid innate immune detection.