Review: Biological and Pharmacological Basis of Cytolytic Viral Activation in EBV-Associated Nasopharyngeal Carcinoma

Abstract

Epstein-Barr virus (EBV) infection contributes to the development of different types of human malignancies, especially nasopharyngeal carcinoma. As a herpesvirus, EBV can establish two major modes of virus-cell interactions: a latent or a lytic infection. Latent infection is prevalent in the vast majority of malignant cells in EBV-related malignancies. Inducing a switch from latent to lytic infection in a substantial fraction of malignant cells has long been considered as a potentially interesting therapeutic approach. Therapeutic benefits are expected from (1) the cytotoxic or cytostatic effects of viral products expressed in the context of the lytic cycle; (2) expression of viral enzymes capable of metabolizing pro-drugs selectively inside these cells and (3) broadening the expression spectrum of antigenic viral proteins. In this chapter, addressing non EBVspecialized readers, we first summarize the main aspects of EBV biology with emphasis on the cellular mechanisms known to control latent and lytic infections. Then, we outline the basic principles and requirements of cytolytic EBV activation performed with a therapeutic intent. Finally, we review the main categories of pharmacological agents reported to be active in the switch from latent to lytic infection, including drugs used for conventional anti-tumour chemotherapy, histone-deacetylase inhibitors and various miscellaneous compounds.

In BRCA1 and BRCA2 Breast Cancers, Chromosome Breaks Occur Near Herpes Tumor Virus Sequences

“…Because virtually everyone carries EBV infection, viral participation in breast cancer is very difficult to distinguish from its role in seemingly normal cells. In general, electron microscopy of EBV associated cancer cells does not detect EBV particles, but malignant cell nuclei do show viral DNA [78] The model based on the present work is potentially actionable. The present evidence adds support for developing EBV treatment and a childhood herpes vaccine.…”

In BRCA1 and BRCA2 breast cancers, chromosome breaks occur near herpes tumor virus sequences

“…Our comparisons of all virus sequences to the human genome reveal widespread, repeated EBV-like variant sequences dispersed throughout the human genome. In general, electron microscopy of EBV associated cancer cells does not detect EBV particles, but malignant cell nuclei do show viral DNA [40] HKHD40 and HKNPC60 herpes viruses can exist as covalently closed circular episomes with multiple copies. These viral genomes assemble into chromatin, undergoing epigenetic histone and DNA modifications analogous to host genomes.…”

EBV-associated diseases: Current therapeutics and emerging technologies

“…One therapeutic approach is therefore the induction of EBV lytic replication, also known as cytolytic virus activation (CLVA), in combination with antiviral drugs to enable specific targeting of tumor cells that harbor EBV in a lytic state ( 18 , 335 ). CLVA within infected tumor cells can induce i) a cytotoxic or cytostatic effect from the lytic viral proteins; ii) expression of viral enzymes that metabolize and activate antiviral pro-drugs, such as ACV and GCV; and iii) a range of antigenic viral proteins that can now be recognized by host-immune cells ( 336 ) ( Figure 4 ).…”