title: The viral interferon regulatory factors of kaposi's sarcoma-associated herpesvirus differ in their inhibition of interferon activation mediated by toll-like receptor 3.
abstract: 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 (IFN) regulatory factors (IRFs), known as viral IRFs (vIRFs). We demonstrate here 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 IFN transcription reporters. However, only vIRF1 and vIRF2 inhibited increases in both IFN-β message and protein levels following TLR3 activation. The 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. Altogether, this report indicates that vIRFs are able to block IFN mediated by TLRs but that each vIRF has a unique function and mechanism for blocking antiviral IFN responses.
authors.affiliation: Lineberger Comprehensive Cancer Center and Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Jacobs
authors.forename: Sean M
authors.initials: SM
authors.lastname: Gregory
authors.forename: John A
authors.initials: JA
authors.lastname: West
authors.forename: Amy C
authors.initials: AC
authors.lastname: Wollish
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Bennett
authors.forename: David J
authors.initials: DJ
authors.lastname: Blackbourn
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.forename: Blossom
authors.initials: B
authors.lastname: Damania
mesh_terms: D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism*; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D050835:Interferon Regulatory Factors; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D007372:Interferons