Scientists at the Icahn School of Medicine at Mount Sinai (ISMMS) say recent research has shed light on the response of the hepatitis C virus (HCV) to targeted therapeutics and provided new insights about HCV’s role in cancer development. Their work (“Hepatitis C virus genetics affects miR-122 requirements and response to miR-122 inhibitors”), published in Nature Communications, focused on microRNA genes, a type of regulatory gene, and used whole-genome sequencing of the virus to challenge conventional wisdom about how the virus responds to emerging therapies.
Their findings, note the researchers, may contribute to more effective development of hepatitis C drugs in the future and to more personalized treatment for patients.
According to the Centers for Disease Control and Prevention, HCV is widespread, affecting some 3% of the world’s population and more than 3 million people in the United States alone. Recent CDC reports indicate that hepatitis C infections are on the rise among young people and are increasingly the cause of death among baby boomers.
The vast majority of people who get HCV will suffer chronic infection, which can lead to liver inflammation, cirrhosis, and liver cancer. Highly effective new treatments have been launched recently, but their high prices have caused public outcry and limited widespread use. There is no commercially available vaccine for hepatitis C.
In this new study, Mount Sinai researchers examined HCV response to an experimental treatment that targets and blocks the supply of a microRNA (miR-122) that the virus needs for infection of human cells. Contrary to expectations, they found that depleting the supply of miR-122 could trigger drug resistance with the emergence of HCV strains able to infect cells with negligible levels of the microRNA. This information could be used for more effective dosing of drugs targeting this gene, as well as for pre-treatment analysis to determine which patients may respond best to this class of drugs.
“This effort, which was made possible by innovative microRNA analysis, offers significant progress toward precision medicine in treating HCV patients,” said Matthew Evans, Ph.D., assistant professor of microbiology at the ISMMS and a co-author of the study. “There is a critical need for more weapons in our arsenal to fight HCV, particularly for affordable, effective treatment as we try to stay a step ahead of this virus and prevent it from developing the kind of drug resistance we’re seeing in the bacterial realm.”
In another key finding, the scientists uncovered knowledge that may help answer the longstanding question of how HCV leads to cancer. The study demonstrated that HCV hijacks the miR-122 gene, diminishing its normal activity in liver cells. Since this microRNA is known to be a potent tumor repressor, it is possible that HCV robs cells of their natural defenses against uncontrolled growth. Such an outcome could contribute to cancers that arise from chronic HCV infection.
“We found that HCV itself reduces miR-122’s activity in the cell, possibly through binding and sequestering miR-122,” wrote the investigators. “Our study provides insight into the interaction between miR-122 and HCV, including viral adaptation to reduced miR-122 bioavailability, and has implications for the development of anti-miR-122-based HCV drugs.”
“Our study offers broader implications for this class of microRNA genes and their interaction with targets, which may be useful for a number of diseases in addition to hepatitis C,” said Brian Brown, Ph.D., associate professor of genetics and genomic sciences at the ISMMS and a co-author of the study. “We are also intrigued by this new information that may shed light on the link between HCV and the onset of cancer and look forward to future efforts to explore this theory.”