Fighting Hepatitis C Virus, Using Clues from What Killed Bevo XIV

Scientists studying the cattle virus that killed a beloved University of Texas mascot nearly three years ago have stumbled upon a discovery that may help unlock treatments for a virus that poses a major threat to people: hepatitis C virus, which kills nearly 20,000 Americans a year. The new research, out this week in the Proceedings of the National Academy of Sciences and led by associate professor of molecular biosciences Christopher Sullivan, sheds light on how human defenses fight off hepatitis C virus infections.

​Sullivan and his team were studying the bovine leukemia virus, the agent that killed Bevo XIV, when they uncovered a naturally occurring protein that is used by the virus to its own benefit to produce viral RNAs that likely contribute to the cancer caused by that virus. They went on to test the protein, however, in the human tumor virus hepatitis C, and found it led to a very different effect: powerfully curbing replication of the virus.

"We found a previously unknown restriction factor—something a patient's body produces to regulate the virus—that helps control hepatitis C virus, and that may have relevance to an emerging drug class for that virus," Sullivan said. "And I think the real interesting story is that a bovine virus that nobody pays enough attention to and is near impossible to get research funding for, led to it all."

More than 3 million people in the United States are living with chronic hepatitis C virus infection, and it is a leading cause of death from infectious disease in the U.S., killing more people than HIV, tuberculosis and pneumonia combined. Hepatitis C virus, or HCV, is transmitted through contact with infected blood and causes inflammation of the liver, leading to cirrhosis and even liver cancer.

Of those exposed to the virus, about 70 percent will suffer from a chronic infection. There is limited understanding of why some people naturally clear the virus and why others live for years without severe liver damage.

Understanding the body's natural defenses and the mechanisms of the disease is essential for developing the best treatments and understanding how the disease progresses, Sullivan notes. Current treatments for hepatitis C are among the most expensive medications on the market, and finding alternatives—including new drugs that harness basic researchers' findings about how the virus works—could help more people to receive treatment.

The researchers discovered how defense mechanisms in the body engage in something of an arms race with HCV. Scientists already knew the first part of this story: the body uses a host enzyme, XRN, to break down HCV RNA transcripts, and then the virus evolves a strategy to prevent XRNs from killing it. Sullivan's team added a twist to the story, locating the protein in the liver, DUSP11, that allows some patients to defeat the virus' tricks and keep XRNs on the job of shutting down infection.

A new HCV drug, currently in phase II clinical trials, targets part of the virus' counter-defense mechanism that the new research helps to explain.

Another promising aspect of the discovery that researchers hope to explore next is whether DUSP11 could dial back inflammation in the liver that leads to conditions like cirrhosis and cancer.

How another virus hides in the body

In another paper out this week, the Sullivan lab announced a separate discovery about how a different type of cancer-causing virus, papillomavirus, persists in humans. That study was published today in the open-access journal PLOS Pathogens and was written by Sullivan and colleagues, including first author and former Ph.D. student Rachel Chirayil, and scientists at the Heinrich Pette Institute in Germany and the Zoological Society of London.

Human papillomaviruses virus (HPV) can cause several types of cancer, including cervical cancer, but it remains unclear why only some infections lead to the development of malignant tumors. Answering this question requires characterizing these viruses' gene products and their role in the life cycle of the viruses.

MicroRNAs are small RNAs that regulate a range of biological processes, including host-pathogen interactions. Viruses that lead to long-term persistent infection often encode microRNAs as a result. (In fact, they factor into how hepatitis C, in the example above, fights off defensive XRN enzymes).

Up until now, however, no microRNAs had been discovered that are made by HPV—in part because there wasn't a good laboratory model for finding them.

For the new research, the team developed a new lab technology, called microRNA Discovery by forced Genome Expression (miDGE), which screens the genomes of viruses in parallel and identifies associated microRNAs. Using miDGE, they screened more than 73 different papillomavirus genomes for the ability to encode microRNAs.

Most papillomaviruses do not appear to code for microRNAs, but the researchers uncovered five new highly probable papillomavirus-encoded microRNAs. Although the papillomavirus microRNAs are not expressed in cancers associated with high-risk infection, some of them control viral gene expression in a way that the cancer-associated HPVs were previously shown to use host microRNAs for. According to the authors, these findings underscore that microRNAs are important regulators of the papillomavirus life cycle.

And as with the bovine leukemia/Hepatitis C virus study, this research, too, involved exploration of a similar virus that affects animals – this time, birds.

"The most important aspect of this work is that this new technology opens up parallel study of numerous pathogens in a single experiment," Sullivan said, "allowing for deep evolutionary cross comparisons. Here, insight from a bird virus helped us to understand why some human papillomaviruses do, and just as importantly, why most don't, encode their own microRNAs."

Sullivan is a researcher with UT Austin's Center for Systems and Synthetic Biology and the LaMontagne Center for Infectious Disease. Other researchers on the hepatitis C paper included Chirayil, Rodney Kincaid and Victor Lam, all of UT Austin, and Glenn Randall of the University of Chicago.

Other authors on the papillomavirus paper besides Sullivan and Chirayil, were Kincaid, Christine Dahlke, Chad Kuny, Nicole Dalken, Michael Spohn, Becki Lawson and Adam Grundhoff.

Both projects were supported by the Burroughs Wellcome Fund and the Cancer Prevention and Research Institute of Texas. The papillomavirus research also received funding support from the Free and Hanseatic City of Hamburg and the German Federal Ministry of Health (BMG).