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. 2011 Jun 17:2:19.
doi: 10.3389/fimmu.2011.00019. eCollection 2011.

The viral interferon regulatory factors of KSHV: immunosuppressors or oncogenes?

Sarah R Jacobs  1 , Blossom Damania
Affiliations

The viral interferon regulatory factors of KSHV: immunosuppressors or oncogenes?

Sarah R Jacobs et al. Front Immunol. .

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a large double-stranded DNA gammaherpesvirus, and the etiological agent for three human malignancies: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. To establish and maintain infection, KSHV has evolved unique mechanisms to evade the host immune response. Cellular interferon regulatory factors (IRFs) are a critical part of the host anti-viral immune response. KSHV encodes four homologs of IRFs, vIRF1-4, which inhibit the activity of their cellular counterparts. vIRF1, 2, and 3 have been shown to interact directly with cellular IRFs. Additionally, the vIRFs have other functions such as modulation of Myc, p53, Notch, transforming growth factor-β, and NF-κB signaling. These activities of vIRFs may contribute to KSHV tumorigenesis. KSHV vIRF1 and vIRF3 have been implicated as oncogenes, making the understanding of KSHV vIRF function vital to understanding KSHV pathogenesis.

Keywords: HHV-8; KSHV; vIRF.

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Figures

Figure 1
Figure 1
Kaposi’s sarcoma-associated herpesvirus vIRFs bind to cellular proteins, block transcription, and interfere with interferon and cellular signaling pathways. Viral infection activates cellular IRFs, including IRF1, 3, 5, and 7 to initiate IFN transcription. Binding of cellular IRFs by vIRF1 or vIRF3 results in a blockade of IFNα, β, and γ transcription. vIRF1 inhibits type I IFN transcription by binding the CBP/p300 transcriptional coactivator and inhibiting its activity. Viral infection also induces NF-κB transcription that is decreased by vIRF3. vIRF1, 3, and 4 inhibit p53 transcription and impede p53-mediated cell death. Other cell death processes affected by vIRFs include vIRF1 binding to GRIM19, vIRF3 interaction with 14-3-3 and FOXO3a, vIRF1 and 2 blockade of CD95L production, and vIRF1-mediated nuclear localization of Bim. In addition to deregulating immune responses and cell death, vIRFs have other roles such as vIRF3 increasing Myc and HIF-1α transcription and blocking expression of MHC II. vIRF1 blocks TGF-β signaling through binding to Smad3 and Smad4 and vIRF4 binding to the Notch transcription factor, CSL/CBF1 to inhibit activation of Notch target genes.
Figure 2
Figure 2
Map of vIRF gene locus in the KSHV genome. The KSHV vIRF genes are encoded by open reading frames K9 (vIRF1), K11 and K11.1 (vIRF2), K10.5 and 10.6 (vIRF3), and K10 (vIRF4).
Figure 3
Figure 3
Homology of vIRFs with cellular IRFs. Cellular interferon regulatory factors (IRFs) are composed of a DNA-binding domain (DBD; green) and a regulatory domain (blue). The DBD of cellular IRFs is defined by 5 tryptophan (W) residues. Cellular IRFs may also contain an IRF-association domain (IAD) shown in yellow. Gray boxes indicate domains in the cellular IRF proteins that are homologous to each KSHV vIRF as determined by NCBI BLAST protein analysis (National Center for Biotechnological Information).
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