The human myxovirus resistance proteins MxA and MxB are expressed upon stimulation with type I and type III interferons (IFNs) in response to viral infection. While MxA is well-known to elicit potent antiviral activity against many viruses, MxB has long been unrecognized to serve any antiviral function. Recently, a potent antiviral effect of MxB against human immunodeficiency virus type 1 (HIV-1) and other primate lentiviruses has been discovered. Evolutionary analyses then indicated that MxB is likely to exert inhibitory activities against additional viruses.
To test this hypothesis, we selected herpes simplex virus type 1 (HSV-1) as a representative of nuclear-replicating large DNA viruses. We first utilized T98G cells as a model due to their high endogenous MxB expression. Then, we tested MxB in absence of other IFN-induced genes by generating A549 cells stably overexpressing MxB (A549-MxB).
We observed that silencing of MxB expression in IFN-treated T98G cells partially rescued HSV-1 replication. Moreover, HSV-1 replication was strongly inhibited in A549-MxB cells as compared to control cells. In line with this, HSV-1 replication in A549-MxB cells recovered to a large extent after siRNA-mediated knock-down of MxB. Similar results were obtained using HSV-2 and Kaposi’s sarcoma-associated herpesvirus (KSHV). Further experiments showed that MxB acts early upon infection, i.e. prior to viral immediate-early gene expression. Accordingly, transmission electron microscopy of incoming HSV-1 capsids revealed an impairment of HSV-1 genome uncoating in cells expressing MxB.
In conclusion, out data indicate that MxB interferes with nuclear entry of herpesviral DNA, suggesting a gatekeeper function of MxB at the nuclear pore.