The KSHV vIRFs differ in their inhibition of interferon activation mediated by TLR3

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is correlated with three human malignancies and can establish lifelong latent infection in multiple cell types within its human host. In order to establish and maintain infection, KSHV utilizes multiple mechanisms to evade the host immune response. One such mechanism is the expression of a family of genes with homology to cellular interferon regulatory factors (IRFs), known as viral IRFs (vIRFs). We demonstrate that KSHV vIRF1, 2, and 3 have a differential ability to block type I interferon signaling mediated by Toll-like Receptor 3 (TLR3), a receptor we have previously shown to be activated upon KSHV infection. vIRF1, 2, and 3 inhibited TLR3-driven activation of interferon (IFN) transcription reporters. However, only vIRF1 and 2 inhibited increases in both IFNβ message and protein following TLR3 activation. Expression of vIRF1 and vIRF2 also allowed for increased replication of a virus known to activate TLR3 signaling. Furthermore, vIRF1 and vIRF2 may block TLR3-mediated signaling via different mechanisms. Together, this report indicates that vIRFs are able to block IFN mediated by TLRs, but that each vIRF has a unique function and mechanism to block antiviral IFN responses.