Viral and host factors drive a type 1 Epstein–Barr virus spontaneous lytic phenotype

Abstract

ABSTRACT Epstein–Barr virus (EBV) is a cancer and autoimmune disease-associated gamma-herpesvirus that infects the majority of adults worldwide. After initial infection, EBV generally maintains a latent state in the host with minimal viral gene expression. However, aberrations in this prototypical latent viral state leading to increased lytic replication can cause upregulation of oncogenic factors, promoting EBV-associated diseases. For example, nasopharyngeal carcinoma and post-transplant lymphoproliferative disease have strong associations with EBV lytic replication. Another EBV-associated disease, endemic Burkitt lymphoma (BL), is an extremely fast-growing cancer found primarily in children in malaria-endemic regions of Sub-Saharan Africa. Nearly all endemic BL tumors are infected with EBV and the hallmark of the disease is high levels of oncogenic c-Myc expression due to an immunoglobulin/ Myc translocation. In this study, we describe spontaneous lytic phenotypes in EBV strains isolated from Kenyan BL patient tumors. We specifically focus on a novel Type 1 spontaneously lytic EBV strain and describe viral and host factors that could contribute to this phenotype. We found that cells infected with spontaneous lytic strains have lower c-Myc protein stability and express high levels of the plasma cell marker SLAMF7. Additionally, spontaneous lytic strains have altered latency states, which appear to further promote their lytic phenotypes. The isolation of spontaneously lytic EBV strains from endemic BL tumors provides more evidence that EBV may not maintain a prototypically latent state in patients with EBV-associated diseases and raises the possibility that promiscuous lytic activity may contribute to the formation of these diseases. IMPORTANCE Epstein–Barr virus (EBV) infects over 95% of adults worldwide. Given its connection to various cancers and autoimmune disorders, it is important to understand the mechanisms by which infection with EBV can lead to these diseases. In this study, we describe an unusual spontaneous lytic phenotype in EBV strains isolated from Kenyan endemic Burkitt lymphoma patients. Because lytic replication of EBV has been linked to the pathogenesis of various diseases, these data could illuminate viral and host factors involved in this process.