How cells are foiled by a herpesvirus family member in the virus-host arms race

In order to do so, the virus has to find a way to enter the cells of the human body without tripping the alarm, and stay there without notice. It's how HIV works, and also how viruses in the herpesvirus family, like human cytomegalovirus (HCMV), do their business.

In a new study published in Science Advances, a group of University of Wisconsin-Madison researchers show that individual cells in the human body have an armament designed to prevent HCMV from achieving and maintaining this latency, to shine a spotlight on the virus so the immune system knows to fight. But the virus, in turn, has developed ways to thwart these defenses.

"We call it an arms race," says study leader Rob Kalejta, professor of molecular virology and oncology at UW-Madison. "Virus evolves a mechanism to persist, human cells evolve a way to defeat that mechanism, virus evolves a way to defeat what the cell just evolved."

The study shows there are potential ways to intervene in that process, says Albright. Its co-lead authors are UW-Madison graduate student Emily Albright and former postdoctoral researcher Song Hee Lee.

HCMV infects people at high rates all around the world. People with compromised or weakened immune systems are especially vulnerable. In newborn babies, the virus can cause deafness, intellectual disability and learning disorders. Other viruses in the herpesvirus family can cause cancer, shingles and mononucleosis. Once people are infected, they will have the virus their entire lives, due to its ability to cycle between latent and active states in the body.

"Our immune system does a pretty good job at fighting lytic (active) herpesviruses, but it has no chance against the latent reservoir," says Kalejta.

The human immune system is made of two main branches: innate and adaptive. One is more general -- the immediate response to a cut in your skin -- and the other more specialized, responding specifically to a variety of pathogens that invade the body. But there is a third, more recently described, arm called intrinsic immunity, where individual cells in the body protect themselves from infection without calling on the body's immune defenses.

Active HCMV is obvious to the body's innate and adaptive immune systems, producing proteins and other viral material that serve as red flags to the body's security system.

But latent HCMV shuts down the processes that allow it to be found.

Previous studies in the lab showed that once HCMV is inside the cell, it quickly becomes latent by entering the cell's nucleus and co-opting a cellular protein called Daxx -- part of the intrinsic immune system -- to shut down its own replication, the process of reproducing its genetic material to make more copies of itself. This process would otherwise trigger a healthy immune system to respond. Instead, it can hide and wait for a time when a person's immune system is weakened.

In the new study, expanding upon what scientists previously understood about intrinsic immunity, the researchers found that cells can subsequently respond to latent HCMV by employing other cellular proteins called lysine demethylases to reactivate the virus.

"When you think about defending yourself against a virus, you usually think about turning it off, but this is what the virus wants to do when it goes latent," Kalejta says. "So this intrinsic immune system is trying to convert it from a latent to a lytic infection so that we at least have a fighting chance against it."

But the wily virus fights back.

The research team learned the virus brings with it to the cell a protein called UL138 that blocks the cellular lysine demethylases from turning the virus back on.

"We showed that UL138 prevents the cellular proteins from getting to the viral genome, and if they can't get there, they can't turn it on," says Albright.

The researchers are not yet sure how UL138 accomplishes this. The cellular proteins are located in the nucleus of the cell, where the virus maintains its genetic material. But UL138, the viral protein, is actually located outside the nucleus, at a cellular component called the Golgi. The viral protein outside the nucleus is somehow preventing the cellular proteins in the nucleus from accessing the viral genome, which is also in the nucleus.

"We'd like to know how that works," Albright adds.

The study of HCMV is revealing new ways in which human cells function, highlighting the role of proteins and other factors that have never been described in these ways before. It is opening new avenues of scientific inquiry.

"We've shown that cells can defend themselves against latent viruses," says Kalejta.

"So if cells can do that, maybe scientists can, too. We are years away from that, but it gives us hope that cures are possible."

The study was also co-authored by UW-Madison researchers Jeong-Hee Lee and Derek Jacobs and funded by the National Institutes of Health.