Kaposi's sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression.

Sandra Koch,Antonio Gallo,Werner Tegge,Wolfram Brune,Elias Hage,Modester Damas,Anika Freise,Jessica Rückert,Elisabeth Kremmer,Akshay Dhingra,Thomas F Schulz,Mark Brönstrup,Dirk P Dittmer

doi:10.1371/journal.ppat.1007743

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) belongs to the subfamily of Gammaherpesvirinae and is the etiological agent of Kaposi’s sarcoma as well as of two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman disease. The KSHV life cycle is divided into a latent and a lytic phase and is highly regulated by viral immunomodulatory proteins which control the host antiviral immune response. Among them is a group of proteins with homology to cellular interferon regulatory factors, the viral interferon regulatory factors 1–4. The KSHV vIRFs are known as inhibitors of cellular interferon signaling and are involved in different oncogenic pathways. Here we characterized the role of the second vIRF protein, vIRF2, during the KSHV life cycle. We found the vIRF2 protein to be expressed in different KSHV positive cells with early lytic kinetics. Importantly, we observed that vIRF2 suppresses the expression of viral early lytic genes in both newly infected and reactivated persistently infected endothelial cells. This vIRF2-dependent regulation of the KSHV life cycle might involve the increased expression of cellular interferon-induced genes such as the IFIT proteins 1, 2 and 3, which antagonize the expression of early KSHV lytic proteins. Our findings suggest a model in which the viral protein vIRF2 allows KSHV to harness an IFN-dependent pathway to regulate KSHV early gene expression.

Highlights

Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) belongs to the genus Rhadinovirus within the subfamily of Gammaherpesvirinae
The KSHV vIRF2 protein regulates viral early gene expression funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Several KSHV vIRFs have been reported to act as interferon antagonists that counteract the induction of the IFN pathway or the expression of interferon stimulated genes (ISGs) [35, 39, 59, 61, 63], vIRF3 has been shown to mediate the degradation of Promyelocytic leukemia nuclear bodies (PML NBs) [44, 45]

Summary

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) belongs to the genus Rhadinovirus within the subfamily of Gammaherpesvirinae. These latent proteins function as viral regulators enabling the establishment and maintenance of latency as well as the inhibition of the lytic cycle They are involved in cell proliferation, survival, differentiation and transformation as well as angiogenesis and the induction of interferon stimulated genes (ISGs) and thereby contribute to KSHV pathogenesis [4,5,6,7]. Viral co-infections with human immunodeficiency virus-1 (HIV-1), Herpes simplex virus (HSV) or Human cytomegalovirus (HCMV) are known to induce KSHV reactivation [13, 16,17,18,19] Several chemical compounds, such as histone deacetylase (HDAC) inhibitors like sodium butyrate (SB), or 12-O-tetradecanoylphorbol-13-acetate (TPA) can activate the lytic replication cycle [20, 21]. Several viral proteins expressed during the early stages of the lytic replication cycle such as vIL6, vGPCR, K1 and K15 contribute to KSHV pathogenesis by promoting proliferation, angiogenesis, invasiveness and may counteract the host antiviral immune response [24, 25]

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