Abstract
Many lymphoproliferative disorders (LPDs) are considered “EBV associated” based on detection of the virus in tumor tissue. EBV drives proliferation of LPDs via expression of the viral latent genes and many pre-clinical and clinical studies have shown EBV-associated LPDs can be treated by exploiting the viral life cycle. After a brief review of EBV virology and the natural life cycle within a host we will discuss the importance of the viral gene programs expressed during specific viral phases, as well as within immunocompetent vs. immunocompromised hosts and corresponding EBV-associated LPDs. We will then review established and emerging treatment approaches for EBV-associated LPDs based on EBV gene expression programs. Patients with EBV-associated LPDs can have a poor performance status, multiple comorbidities, and/or are immunocompromised from organ transplantation, autoimmune disease, or other congenital or acquired immunodeficiency making them poor candidates to receive intensive cytotoxic chemotherapy. With the emergence of EBV-directed therapy there is hope that we can devise more effective therapies that confer milder toxicity.
Highlights
Epstein-Barr Virus (EBV), called human herpesvirus 4 (HHV-4), is a lymphotropic gamma-herpes virus that infects >90% of adults worldwide [1]
The BARTs are a group of stable viral RNAs represented in every EBV infected cell type
Their expression is regulated by promoter methylation and treatment with a DNA methyltransferase increased the expression of BART miRNA transcripts [89]
Summary
Epstein-Barr Virus (EBV), called human herpesvirus 4 (HHV-4), is a lymphotropic gamma-herpes virus that infects >90% of adults worldwide [1]. LMP2A is implicated in the development of Hodgkin lymphoma via specific alterations in gene transcription [75] These examples highlight how EBV machinery can subvert the cell’s normal epigenetic mechanisms thereby promoting viral latency and subsequent tumorigenesis. The BARTs are a group of stable viral RNAs represented in every EBV infected cell type Their expression is regulated by promoter methylation and treatment with a DNA methyltransferase increased the expression of BART miRNA transcripts [89]. These lytic viral proteins can suppress pro-inflammatory cytokine release and temper the innate immune response including natural killer cell killing of EBV-infected B-cells [108] This detailed knowledge of the viral life cycle provides opportunities to target features of the virus that promote lymphoproliferation. Though, we expect and look forward to future treatment approaches that will be more specific based on the improved understanding of the viral life cycle, including epigenetic modifications, outlined above
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