Journal
JOURNAL OF VIROLOGY
Volume 85, Issue 9, Pages 4530-4537Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02123-10
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Funding
- Akademie der Wissenschaften und der Literatur (Mainz)
- European Community
- Deutsche Forschungsgemeinschaft graduate school
- Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg
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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-gamma)-sensitive CIITA promoters PIV and PIII were inhibited by vIRF-3. Consistently, IFN-gamma levels increased upon vIRF-3 knockdown in PEL cells. IFN-gamma regulation by vIRF-3 was confirmed in reporter assays as well as by upregulation of typical IFN-gamma 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-gamma and CIITA and thus MHC II expression.
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