Agents and Approaches for Lytic Induction Therapy of Epstein-Barr Virus Associated Malignancies

Abstract

Epstein-Barr virus (EBV) is causally associated with multiple cancers of epithelial and lymphoid origin. Generally, EBV establishes a lifelong quiescent homeostasis (latency) exerting its immune modulating and oncogenic properties only under certain conditions. Lytic replicative EBV infection is restricted to differentiated oropharyngeal epithelia and plasma B-cells. In EBV-associated tumor cells viral gene expression is limited to defined latency programs, without overt virus replication. Artificial triggering of EBV lytic replication with chemical agents (drugs) forms the basis of cytolytic virus activation (CLVA) therapy currently under clinical investigation for treating EBV-positive malignancies. Reactivation from latency requires expression of viral transactivator proteins BZLF1 (Zta) and BRLF1 (Rta). In tumor cells, the BZLF1 promoter (Zp) is highly methylated and generally inactive. However, Zp can be triggered into a self-enhancing activation loop in response to chemical or biological agents, including cytostatic drugs and epigenetic modifiers. This process is orchestrated by Zp-binding cellular transcription factors, such as myocyte enhancer factor 2 (MEF2), specificity protein 1 (SP1), and zinc finger E-box binding homeobox (ZEB) proteins. Understanding the mechanism of lytic induction by chemical inducers is essential for developing effective therapies. This review provide a short overview of EBV biology and will focus on branded and novel agents (drugs) used for EBV lytic induction and discuss molecular mechanisms by which the EBV lytic switch is triggered and controlled.