Researchers at NIH reported that alcohol increases replication of the hepatitis C virus (HCV) in human cells and, by so doing, may contribute to the rapid course of HCV infection. The researchers tested the actions of alcohol in HCV replicon - viral HCV-ribonucleic acid or HCV-RNAs that, when introduced into human liver cell lines, replicate to high levels. In separate laboratory experiments they showed that
-- alcohol increases HCV replication at least in part by upregulating a key cellular regulator of immune pathways and function known as nuclear factor kappa B;
-- alcohol inhibits the anti-HCV effect of interferon-alpha therapy; and
-- treatment with the opioid antagonist naltrexone abolishes alcohol actions.

Speculating that alcohol somehow promotes HCV expression, the researchers relied on a recently available cellular system for studying the dynamics of virus replication (developed and provided to the investigators by Drs. C. M. Rice, The Rockefeller University, and Christoph Seeger, Fox Chase Cancer Center) to demonstrate for the first time that alcohol enhances HCV replicon expression at both the messenger RNA and protein levels. In the cell lines used for the study, the research team also showed that alcohol activation of nuclear factor kappa B was responsible for increasing HCV expression. "Although the replicon system mimics only some aspects of HCV replication, we have identified at least a likely mechanism whereby alcohol increases viral load and thus may become an important cofactor in HCV severity," Dr. Douglas said.

"These findings are immediately useful to clinicians for counseling HCV-positive patients about alcohol use," said Ting-Kai Li, Director, National Institute on Alcohol Abuse and Alcoholism (NIAAA). "For clinical and basic scientists, they raise new research questions, many of which no doubt will be explored using the model and methods introduced today." NIAAA supported the experiments through a grant to Dr. Douglas, whose work also was supported by the National Institute of Mental Health and the National Institute on Drug Abuse (NIDA). The NIAAA and NIDA supported Dr. Ho's work on the study.

HCV is an RNA virus of the flavivirus family that infects about 4 million U.S. residents and produces some 30,000 new infections each year. HCV typically escapes clearance by the immune system and leads to persistent, chronic infection in 70 to 85 percent of infected individuals, of whom fewer than 50 percent respond to interferon-alpha, the HCV therapy of choice. Over the long term, HCV infection can lead to cirrhosis, liver failure, and liver cancer. As a group, HCV-infected individuals are the major recipients of liver transplantation.

Clinicians have long observed a high incidence of HCV infection in heavy drinkers, including those without other risk factors such as intravenous drug abuse or history of blood transfusions. In addition, the virus is more likely to persist in heavy drinkers and to lead to such complications as cirrhosis and liver cancer. Suspected mechanisms for the latter effects include alcohol's capacity to compromise immune function and enhance oxidative stress. The role of alcohol use in HCV acquisition has been more of a mystery.