Scientists at Jefferson Medical College may have helped devise a new way to fight the hepatitis B virus (HBV). Timothy Block, Ph.D., professor of biochemistry and molecular pharmacology and medicine at Thomas Jefferson University in Philadelphia, and his colleagues at several institutions have found that by interfering with a specific step in the life cycle of the woodchuck hepatitis virus, the virus can't reproduce, shutting down its ability to infect a cell.
By blocking the creation of a virus "envelope", the virus DNA is locked within the infected cell. As a result, levels of the virus in the animals' bloodstream drop dramatically. The researchers say that the work may provide leads to improved methods of fighting hepatitis B virus (HBV) and hepatitis C (HCV) infections in chronically infected humans.
"This points to a new way to inhibit the hepatitis B virus," says Dr. Block, who is a member of Jefferson's Kimmel Cancer Center and director of the Jefferson Center for Biomedical Research and Agricultural Medicine. Dr. Block and his colleagues report their results in May in the journal Nature Medicine.
"We've discovered that a very specific step in the life cycle of the virus that can be selectively inhibited by a drug, N-nonyl-DNJ," he explains. "It works by inhibiting the first step in the glycosylation process that all cell glycoproteins go through to reproduce and be able to infect. We discovered that the host cellular glycoproteins appear to be far less sensitive to this inhibition than is HBV.
"We were able to inhibit this step in glyco-processing and shut down the appearance of infectious virus in most of the infected animals," he says. "It prevents the appearance of envelope virus in the animals' blood, so it prevents infection.
"This paper introduces another way of inhibiting HBV," he says. "The other ways to inhibit the virus work against an enzyme, viral polymerase. This comes at a different step in the virus life cycle. The virus still makes DNA, but gets stuck in the cell.
"We see a tremendous drop in envelope virus, and the current virus that remains, we believe, would be non-infectious. It still requires more study."
According to Dr. Block, recently, several drugs such as interferon-alpha, have shown promise and have been approved by the Food and Drug Administration to treat HBV. Recently, a drug called lamivudine has been approved to treat the disease. However, the virus can become drug-resistant.
Dr. Block notes that the drug works synergistically with lamivudine, and predicts N-nonyl-DNJ will work against resistant HBV strains as well. Dr. Block also thinks that the drug will be effective against other similar viruses such as HCV. "We've already shown that Bovine diarrhea virus, an accepted tissue culture model of HCV, is completely receptive to this approach," he says.
The next step, he says, is to continue testing the drug in the woodchuck, which is a standard model with which to study HBV. Then researchers will test the drug to see if it is safe in people. In some cases, it has slight side effects such as diarrhea and gastritis.
Acccording to Dr. Block, worldwide, HBV chronically infects some 350 million people. Despite the fact that there is a safe, effective vaccine, as many as 140 million will die from HBV related liver diseases, such as hepatitis, cirrhosis and cancer. For most of the world, HBV is transmitted most often from mother to newborn. However, in the United States, the virus is usually transmitted sexually. It is also transmitted by accidental needle sticks among health care workers. Some one-quarter to one-third of the population that is chronically infected have no known risk factors.
Those at risk for contracting HCV include intravenous drug abusers, and those who had transfusions prior to 1990, when blood supply screening for HCV began.
Scientists from several other institutions participated in the study, including Raymond Dwek, D. Phil., FRSC, Oxford University, and Nobel laureate Baruch Blumberg, M.D., Ph.D, Fox Chase Cancer Center, as well as those from Cornell University, Georgetown University and Monsanto Company.
Journal
Nature Medicine