Viral and Host Factors Drive Spontaneous Reactivation of Type 1 Epstein Barr Virus

Abstract

Epstein Barr virus (EBV) is a gamma-herpesvirus that latently infects the majority of adults worldwide. EBV infection, and particularly lytic replication, is linked to various cancers and autoimmune disorders. For example, endemic Burkitt lymphoma (BL) is an EBV-associated B cell lymphoma that primarily affects children in malaria endemic regions of Sub-Saharan Africa. In this dissertation, I characterize new EBV strains derived from Kenyan BL patient tumors isolated by collaborators in Kisumu, Kenya. Like all herpesviruses, EBV prototypically maintains a tight latency in infected cells until reactivated by an external stimulus, such as B cell receptor crosslinking. However, Type 2 genetic variants of EBV are known to spontaneously enter the lytic cycle. Surprisingly, a Type 1 (T1) BL-derived EBV strain described in this study also spontaneously reactivates and produces virions in culture. We extensively characterized this T1 spontaneous lytic phenotype using molecular and bioinformatic techniques and identified viral and host factors that contribute to the phenotype. Specifically, I determined that a variant of the viral lytic transcription factor RTA increases lytic reactivation, that this lytic phenotype is further enhanced by the virus maintaining a latency III state, and that the T1 spontaneous lytic phenotype is favored in differentiated, plasma-like cells. Overall, the results of this research increase our appreciation of EBV phenotypic diversity and support the possibility that EBV lytic replication is an important factor in EBV associated diseases.