Translating viral infection into liver-cancer protection

An otherwise healthy adult who comes down with the flu might liken the experience to being hit by a ton of bricks. Yet like all illnesses caused by viruses, the disease arises from a tiny parasitic microbe far too small to be seen by the naked eye or even through a standard microscope.

To Dr. Laura Beretta, who moved her laboratory from the University of Michigan to the Public Health Sciences Division in August, these David-vs.-Goliath tales of viral infection are among biology's most fascinating — and mysterious — problems. Beretta's work focuses on the hepatitis C virus, an infection that escapes immune-system detection, causing a chronic infection that often leads to liver cancer.

"Hepatitis C is a tiny virus, consisting of only 10 proteins, and like all viruses it's completely dependent on the host to survive," she said. "But it persists in the body and is responsible for the majority of cases of hepatocellular carcinoma (liver cancer) in the United States. How do 10 proteins manage to cause such damage, and why can't our immune systems eradicate the infection?"

By studying how the hepatitis C virus hijacks the human innate immune system and by studying how the virus uses the host cellular proteins for its replication, Beretta's work could reveal potential targets for drugs that disable the virus' ability to multiply. Her laboratory also is searching for molecules released into an infected person's blood that could provide clues about when and whether a person is likely to develop liver cancer. The work is particularly important given the number of people around the world infected with the virus and the lack of effective diagnostic tests and treatments for liver cancer. There is currently no vaccine to protect individuals from becoming infected, said Dr. John Potter, director of the PHS Division.

"There is much to be discovered about the biology of this virus," he said. "Laura is a key addition to our strength in virology and will also be a player as we establish a program in gastrointestinal cancer. It is terrific to have her with us."

Aftermath of an epidemic

Hepatitis C is the most frequent bloodborne chronic infection in the United States, said Beretta, a native of France. "About 1.8 percent of the U.S. population is infected," she said. "Yet the disease has been poorly studied."

The virus is spread through infected blood. Prior to the development of tests for routine screening of blood donations, many Americans were infected through blood transfusions. About 70 percent to 80 percent of those infected become chronic carriers; subsequently, 30 percent develop liver cirrhosis decades later. About 30 percent of those with cirrhosis develop liver cancer within 10 years, Beretta said.

"The incidence of hepatocellular carcinoma is expected to triple in this country in the next 10 to 20 years as a consequence of the epidemics of hepatitis C infection in the 1960s to 1980s," she said.

Understanding viral evolution

Beretta's work on hepatitis C grew from her longstanding general interest in how some viruses manage to avoid being cleared from the body even by a healthy person's immune system. Unlike microbes such as bacteria or fungi, viruses are not able to survive outside a host. Once inside, viruses multiply by using the host cell's machinery to copy their genetic material and decode it into viral proteins, resulting in the production of many new viruses — and the onset of infection. An infected cell can usually protect itself by shutting off its own system for making proteins, since the virus has no system of its own, and by producing large amounts of interferon. Yet some viruses have evolved a counterattack strategy that blocks the host's defense system.

"We'd like to understand the mechanisms behind how viruses evolve to favor their own replication," she said. "Part of why this is so poorly understood is that we don't have a clear understanding of protein synthesis — a process called translation — even in healthy cells. It's been very understudied compared to the other aspects of gene expression."

Beretta's group discovered that in human immune cells, control of a significant percentage of genes occurs through translation. This finding suggests that translation may be much more important than previously suspected, and that some of the genes controlled in this fashion may be critical in cells undergoing stress such as viral infection. Understanding translational control in more detail, she believes, could open the door to development of new drugs. Several years ago, Beretta discovered that rapamycin, an agent currently used as an immunosuppressant as well as an anti-cancer drug, specifically targets the activity of a protein involved in translational control.

Interferon is often used as a treatment for hepatitis C infection but is not effective for the majority of patients. Beretta and others have discovered clues to how hepatitis C antagonizes the effect of interferon. She also has recently identified host cellular proteins that are directly involved in the replication of the virus. She speculates that it may be possible to develop, based on these findings, drugs that interfere with hepatis C replication.

More recently, Beretta has been intrigued by the possibility of developing blood tests that can predict when and whether a person infected with hepatitis C will develop cancer. The work focuses on identifying proteins, called markers, in the blood serum that provide information about a person's risk, type and stage of liver cancer. Part of her interest in joining Fred Hutchinson's faculty was the center's overall interest in developing tests to detect cancer at its earliest stages, when it is more likely to be curable, as well tests to monitor cancer progression and response to treatment.

Beretta is currently developing tools to measure approximately 50 candidate markers in the blood of 300 hepatitis C-infected individuals who have liver cirrhosis. Patients will be followed over a five-year period, during which time about 15 to 20 percent of them will develop liver cancer. She and colleagues hope to find a subset of markers that are elevated in the patients who develop cancer.

"This is a highly fatal cancer with a median survival time from the date of diagnosis of seven to eight months," she said. "Right now, the only real cure for liver cancer is a liver transplant, but many people are diagnosed too late to be good candidates for transplantation. We hope that our early-detection work, in conjunction with studies to develop new treatments, will improve outcomes for these patients."