Oncovirus Latency Mechanisms Discovered

Merkel cell polyomavirus uses protein-mediated mechanisms to remain latent.

Numerous viruses live dormant in the body without causing harm. A new study published by the Proceedings of the National Academy of Sciences shows how the Merkel cell polyomavirus (MCV) remains dormant for decades after infection prior to activating and causing aggressive skin cancer.

The virus was first discovered by American Cancer Society researchers in 2008. This oncovirus is known to cause Merkel cell carcinoma and is found in a vast majority of tumors. Although this cancer is rare, it is very aggressive.

Viruses typically infiltrate their host’s immune system and either rapidly replicate or find a new host. Some viruses remain in the body without replicating until there are ideal conditions, such as when the host’s immune system is weakened, according to the study.

Other latent viruses, such as herpes simplex viruses, can remain dormant for years and emerge to cause ulcers. Another study found that children diagnosed with acute lymphoblastic leukemia were found to be more than 3 times as likely to have had a herpes infection at birth, compared with children who do not develop the disease. While the virus remains dormant, it can reactivate during pregnancy, but the underlying reasons are unknown.

Herpes viruses use molecular mechanisms to sustain latency, but MCV has a smaller amount of DNA and cannot rely on its own latency mechanism.

In the new study, the authors used cell cultures to determine what methods MCV uses to remain dormant. The authors discovered that MCV takes over the cell’s normal degradation mechanisms to reactivate.

The virus was found to take over SCF E3 ligases, which normally function in the cell to tag cellular proteins that are to be destroyed by the proteasome, according to the study.

“Normally, viruses use elaborate measures to avoid being degraded by the cell so that they can infect a new host,” said researcher Patrick Moore, MD. “But in a form of molecular jujitsu, MCV ensures that a key protein required for its replication is continually degraded so that the virus, retained as a naked piece of DNA, is not eliminated by the proteasome, which only degrades proteins.”

The authors have named this process protein-mediated viral latency, according to the study.

Under adverse conditions, MCV can reactivate due to the suspicion it may need a new host. Cells shut off some SCF E3 ligases when nutrients are lost, which allows the MCV replication protein to increase and create new viruses, according to the study.

During this process, if viral DNA breaks apart, it can merge with cell DNA and lead to Merkel cell carcinoma. However, if the replication is successful, MCV can be transferred to a new host without symptoms.

The authors note that their findings must be confirmed in human tissues. They are currently working to determine whether MCV is the only virus that relies on protein-mediated latency or other viruses also use similar mechanisms, the study concluded.