Entry point for hepatitis C infection identified
A molecule embedded in the membrane of human liver cells that aids in cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according to research at the University of Illinois at Chicago College of Medicine.
The cholesterol receptor offers a promising new target for anti-viral therapy, for which an approved drug may already exist, say the researchers, whose findings were reported online in advance of publication in Nature Medicine.
An estimated 4.1 million Americans are infected with hepatitis C virus, or HCV, which attacks the liver and leads to inflammation, according to the National Institutes of Health. Most people have no symptoms initially and may not know they have the infection until liver damage shows up decades later during routine medical tests.
Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected that a receptor called NPC1L1, known to help maintain cholesterol balance might also be transporting the virus into the cell.
The receptor is common in the gut of many species - but is found on liver cells only in humans and chimpanzees, says Susan Uprichard, assistant professor in medicine and microbiology and immunology and principal investigator in the study. These primates, she said, are the only animals that can be infected by HCV.
Uprichard and her coworkers showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells.
Bruno Sainz, Jr., UIC postdoctoral research associate in medicine and first author of the paper, said because the receptor is involved in cholesterol metabolism it was already well-studied. A drug that “specifically and uniquely targets NPC1L1” already exists and is approved for use to lower cholesterol levels, he said.
Hepatitis C infection facts
HCV is one of several viruses that cause hepatitis (inflammation of the liver).
Up to 85% of individuals who are initially (acutely) infected with HCV will fail to eliminate the virus and will become chronically infected.
HCV is spread most commonly through inadvertent exposure to infected blood. Intravenous drug abuse is the most common mode of transmission. The risk of acquiring HCV through sexual contact is low.
Generally, patients do not develop symptoms of chronic infection with HCV until they have extensive scarring of the liver (cirrhosis). Some individuals, however, may have fatigue and other non-specific symptoms in the absence of cirrhosis. A minority of patients with HCV have symptoms from organs outside of the liver.
In the U.S., Infection with HCV is the most common cause of chronic hepatitis and the most common reason for liver transplantation.
HCV is diagnosed by determining levels in the blood of antibodies to the virus and then confirmed with other tests for viral RNA. The amount of viral RNA in the blood (viral load) does not correlate with the severity of the disease but can be used to track the response to treatment.
A liver biopsy may be used to assess the amount of liver damage (liver cell injury and scarring), which can be important in planning treatment.
Considerable progress has been made in the treatment of HCV, although response rates remain imperfect, approximately 50%-60% for genotype 1. Combined therapy with pegylated interferon and ribavirin is the standard treatment regimen.
Treatment results in reduced inflammation and scarring of the liver in most sustained responders and also occasionally (and to a much lesser extent) in those who relapse or do not respond.
The FDA-approved drug ezetimibe (sold under the trade-name Zetia) is readily available and perfectly targeted to the receptor, Sainz said, so the researchers had an ideal method for testing NPC1L1’s involvement in HCV infection.
They used the drug to block the receptor before, during and after inoculation with the virus, in cell culture and in a small-animal model, to evaluate the receptor’s role in infection and the drug’s potential as an anti-hepatitis agent.
Getting a tattoo could be a key infection route for hepatitis C, the most common chronic viral infection affecting almost 2 percent of the United States population, according to a study by a UT Southwestern Medical Center at Dallas researcher.
Dr. Robert Haley, chief of epidemiology, writes in the March issue of the journal Medicine that tattooing has been previously overlooked as a widespread source of hepatitis C, a potentially fatal disease that attacks the liver, leading to cirrhosis and liver cancer.
The study found that people who had received a tattoo in a commercial tattoo parlor were nine times more likely to be infected with hepatitis C than people who did not have a tattoo.
Participants in the study were patients of an orthopaedic spinal clinic, a setting that provided a large volume of patients seeing a physician for reasons unrelated to blood-borne infection. Participants unaware of their hepatitis status were examined, interviewed for risk factors and tested for hepatitis C by the study’s co-author Dr. Paul Fischer.
Of 626 patients studied, 113, or 18 percent, had a tattoo. Of those with a tattoo, 22 percent were infected with hepatitis C. Of the 52 patients who had acquired their tattoos in commercial tattoo parlors, 33 percent had hepatitis C. In contrast, only 3.5 percent of patients with no tattoos had hepatitis C. Few of the tattoo-associated infections could be traced to injection-drug use, transfusions or other known routes of exposure.
The researchers showed that ezetimibe inhibited HCV infection in cell culture and in mice transplanted with human liver cells. And, unlike any currently available drugs, ezetimibe was able to inhibit infection by all six types of HCV.
The study, Uprichard said, opens up a number of possibilities for therapeutics.
Hepatitis C is the leading cause for liver transplantation in the U.S., but infected patients have problems after transplant because the virus attacks the new liver, Uprichard said.
While current drugs are highly toxic and often cannot be tolerated by transplant patients taking immunosuppressant drugs, ezetimibe is quite safe and has been used long-term without harm by people to control their cholesterol, Uprichard said. Because it prevents entry of the virus into cells, ezetimibe may help protect the new liver from infection.
For patients with chronic hepatitis C, ezetimibe may be able to be used in combination with current drugs.
“We forsee future HCV therapy as a drug-cocktail approach, like that used against AIDS,” Uprichard said. “Based on cell culture and mouse model data, we expect ezetimibe, an entry inhibitor, may have tremendous synergy with current anti-HCV drugs resulting in an improvement in the effectiveness of treatment.”
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The study was supported by NIH Public Health Service grants, the American Cancer Society Research Scholar grant, the UIC Center for Clinical and Translational Science NIH grant, the UIC Council to Support Gastrointestinal and Liver Disease, and a grant from the Ministry of Health, Labor and Welfare of Japan.
Naina Barretto, Danyelle Martin, Snawar Hussain, Katherine Marsh and Xuemei Yu, of UIC; Nobuhiko Hiraga, Michio Imamura and Kazuaki Chayama, of Hiroshima University in Japan; and Waddah Alrefai of UIC and the Jesse Brown VA Medical Center in Chicago also contributed to the study.
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Jeanne Galatzer-Levy
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312-996-1583
University of Illinois at Chicago