title: Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 3 inhibits gamma interferon and major histocompatibility complex class II expression.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) carries four genes with homology to human interferon regulatory factors (IRFs). One of these IRFs, the viral interferon regulatory factor 3 (vIRF-3), is expressed in latently infected primary effusion lymphoma (PEL) cells and required for their continuous proliferation. Moreover, vIRF-3 is known to be involved in modulation of the type I interferon (IFN) response. We now show that vIRF-3 also interferes with the type II interferon system and antigen presentation to the adaptive immune system. Starting with an analysis of the transcriptome, we show that vIRF-3 inhibits expression of major histocompatibility complex class II (MHC II) molecules: small interfering RNA (siRNA)-mediated knockdown of vIRF-3 in KSHV-infected PEL cell lines resulted in increased MHC II levels; overexpression of vIRF-3 in KSHV-negative B cells leads to downmodulation of MHC II. This regulation could be traced back to inhibition of class II transactivator (CIITA) transcription by vIRF-3. Reporter assays revealed that the gamma interferon (IFN-γ)-sensitive CIITA promoters PIV and PIII were inhibited by vIRF-3. Consistently, IFN-γ levels increased upon vIRF-3 knockdown in PEL cells. IFN-γ regulation by vIRF-3 was confirmed in reporter assays as well as by upregulation of typical IFN-γ target genes upon knockdown of vIRF-3 in PEL cells. In summary, we conclude that vIRF-3 contributes to the viral immunoevasion by downregulation of IFN-γ and CIITA and thus MHC II expression.
authors.affiliation: Virologisches Institut, Universitätsklinikum Erlangen, Schlossgarten 4, D-91054 Erlangen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmidt
authors.forename: Effi
authors.initials: E
authors.lastname: Wies
authors.forename: Frank
authors.initials: F
authors.lastname: Neipel
mesh_terms: D017951:Antigen Presentation; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000472:pathogenicity*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D006801:Humans; D057131:Immune Evasion; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D000949:Histocompatibility Antigens Class II; D050835:Interferon Regulatory Factors; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D014764:Viral Proteins; C413486:viral interferon regulatory factors; D007371:Interferon-gamma