How understanding the complex world of herpes viruses can help fight cancer

At the UC Davis Comprehensive Cancer Center, a scientist's sleepless nights are dominated by the mysteries of virus-host interactions. Researcher Yoshihiro Izumiya delves into the complex world of herpes viruses. These viruses often remain dormant for years, then awaken and wreak havoc on their hosts, leading to serious illness and complications.

Herpes viruses are common pathogens with more than 100 known types. Eight of these mainly affect humans. These human herpesviruses (HHVs) include the sexually transmitted herpes simplex viruses (types 1 and 2), Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus (KSHV).

While many people carry these viruses without knowing it, the infections can remain hidden for years before suddenly causing serious health problems.

“Inflicting disease on the host is not a smart thing for pathogens to do. They alert people to their presence and provoke a response from the host's immune system. The smartest viruses simply infect and do not trigger immune responses from the host,” Izumiya said.

Izumiya is a professor in the Department of Dermatology and works as a research assistant at the Cancer Center. His lab studies virus-host interactions, focusing on how herpesviruses transition from dormancy to active replication, which often leads to disease.

Switch from dormant to active replication state

One line of research in the Izumiya Lab relates to the Kaposi's sarcoma herpes virus. This virus is known for its association with Kaposi's sarcoma, a skin cancer, and AIDS-related Castleman disease, a rare disorder involving enlarged lymph nodes.

Izumiya's team is working to understand how chromatin, a genetic material of KSHV, remains in a state ready for reactivation and how it becomes active in response to external stimuli. By studying these mechanisms, they hope to develop treatments that could prevent the virus from reactivating.

“The key to identifying a therapeutic approach for KSHV-associated diseases lies in understanding when and how KSHV begins to replicate from dormant viral chromatin,” Izumiya explained. “We are trying to uncover the mechanisms behind this shift and are focusing on how host inflammation supports KSHV replication and disease development cycles.”

Herpes virus hijacks the cell machinery

The herpes virus is a remarkably complex virus. It cannot reproduce independently outside of infected host cells. Therefore, it controlled the machines of several cells.

Izumiya and his team are studying how KSHV manipulates host cell functions. Researchers have found certain viral proteins that are essential for taking over cellular resources.

In KSHV-infected cells, the virus hijacks the cell's transcription machinery, which produces messenger RNAs (mRNAs). KSHV replication turns off host cell mRNA expression by redirecting cellular resources to produce viral mRNAs. This mechanism prioritizes virus replication.

The team also adopted a “reverse hijacking” strategy and identified a small protein domain called VGN50. VGN50 controls the cell's transcription processes like a viral protein.

“When the virus multiplies, the cell stops growing. The virus essentially takes over the transcription machinery,” Izumiya explained. “By borrowing the virus’s hijacking mechanism with VGN50, we can slow down the cells’ inflammatory responses.”

Recently, Izumiya Lab produced another special peptide called VGN73. VGN73 also aligns with the viral protein's mechanism to limit mRNA production. Their study was published today in Cell chemical biology.

These virus-host interaction research projects have major implications for cancer studies. The team will test the small peptide identified from the KSHV protein sequence to stop the growth of cancer cells. Studies of virus-host interactions are important for finding new drugs, Izumiya said.

Herpes virus associated with neurological diseases

Izumiya's work is not limited to KSHV. His team is also studying herpes viruses 6A and 6B, collectively known as HHV-6A/B. These viruses infect people at a very young age and can integrate into human chromosomes. The viral genome integrates into germ cells and can be passed on from one generation to the next.

“This inherited form of HHV-6A/B occurs in approximately 1-2% of the population in Europe and the United States. The entire viral genome becomes part of every cell chromosome,” Izumiya said.

“Clinical observations suggest that inherited chromosomally integrated HHV-6 (iciHHV-6) is associated with a number of serious health problems. These include brain inflammation, preeclampsia in pregnancy and complications after stem cell transplants.”

The lack of suitable tissue culture models makes the study of iciHHV-6 challenging. That's why Izumiya's team is developing cell models with induced pluripotent stem cells that can become any cell type in the body. They use 32 iciHHV-6 patient samples and generate stem cells. The team plans to differentiate cells into neurons and blood cells to find out when, where and how iciHHV-6 begins replicating.

This work is in collaboration with Tetsushi Yoshikawa, head of the Department of Pediatrics at Fujita Medical University in Japan. The study is supported by the National Institute of Allergy and Infectious Diseases.

Izumiya's research paves the way for potential new treatments for herpes viruses and cancer. By uncovering the secrets of the herpes virus, Izumiya and his team could use the ingenious strategies of one pathogen to combat another disease. Their work underlines the importance of basic medical research.