When the Epstein-Barr virus infects human cells, the virus takes on either its “latent” or “lytic” forms. During a lytic infection, the virus actively produces infectious particles in an effort to spread to other cells. A latent infection typically occurs once the immune system suppresses a lytic infection, and the virus ‘hides’ in host cells, not actively replicating.
But EBV latency isn’t as ‘latent’ as the name might suggest. While the virus is hiding out, part of its genome is being expressed and producing oncogenic proteins that can contribute to cancer formation, and it’s in EBV’s latent form that nasopharyngeal carcinoma (NPC) begins to develop. The nasopharynx is the uppermost part of the throat immediately behind and connected to the nasal cavity.
If that weren’t bad enough, University of Wisconsin-Madison researchers discovered that a certain epigenetic modification of the EBV genome — a change in how DNA is expressed, but not a change to the DNA itself — could make EBV more infectious and revert to its lytic form. The lytic infection allows EBV to spread to many other cells in the nasopharynx, presumably spreading the cancer-causing virus.
The modification, called 5-hydroxymethylation, has never been shown to regulate viral gene expression until now. The cellular proteins that control whether this modification occurs on genes, called TET enzymes, are commonly mutated or deactivated in nasopharyngeal carcinoma.
“What we’ve discovered is that this modification can occur on the EBV genome and it affects how EBV is regulated,” said Dr. Shannon Kenney, professor in the departments of oncology and medicine in the UW School of Medicine and Public Health. “It’s important because this is the first virus where this modification has been shown to occur and regulate it. We know that patients who have NPC have very high levels of antibodies to EBV proteins that are expressed only in the lytic form of infection, so we know that they’ve had recent high-level lytic infection before developing NPC.
“We think that latent infection contributes to NPC at later stages, but we believe that lytic infection, which occurs early in NPC development, is also required for formation of this tumor because it helps the virus spread. We showed that loss of TET activity in EBV-infected cells helps to induce the latent to lytic switch and produce more infectious viral particles.”
EBV, which causes infectious mononucleosis as well as a number of cancers, is one of the most common viruses in humans. It is transmitted through bodily fluids like saliva, and up to 95 percent of adults have specific viral antibodies that suggest they either have or have had an EBV infection.
While most people overcome an EBV infection as they would a common cold, it’s most dangerous to people with compromised immune systems or during serious infections that tax the immune system.
“The cellular TET enzymes are increasingly recognized to be important for preventing a number of human cancers including glioblastoma, various types of leukemia and now perhaps EBV-induced NPC as well,” said Kenney. “That’s why we started to look and see if the loss of this modification on DNA is not only important for regulation of the cellular genes but also for what the EBV virus does in the cell. We know EBV is required for NPC, but this epigenetic modification really affects how the virus behaves.”
This study, published in December 2015 by PNAS, was a collaborative effort between three UW faculty members including Kenney, who is also an infectious-disease clinician; Dr. Eric Johannsen, department of medicine; and Paul Lambert, chair of the department of oncology and director of the McArdle Laboratory for Cancer Research. All three are members of the UW Carbone Cancer Center.
Other authors of the study included graduate students Coral Wille, Dhananjay Nawandar and Amanda Henning, associate researcher Denis Lee, research scientist Shidong Ma, and undergraduate Kayla Oetting.
University of Wisconsin School of Medicine and Public Health