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Research on hepatitis C infection could lead to new treatment

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Susan Uprichard

A molecule that allows the entry of the hepatitis C virus is found on liver cells in humans and chimpanzees, says College of Medicine researcher Susan Uprichard.

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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 researchers in the 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 initial symptoms and may not know they have the infection until liver damage shows up decades later in routine medical tests.

Previous studies showed that cholesterol was somehow involved in HCV infection. The UIC researchers suspected a receptor called NPC1L1, known to help maintain cholesterol balance, might 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, said principal investigator Susan Uprichard, assistant professor of medicine and microbiology and immunology.

These primates, Uprichard said, are the only animals that can be infected by HCV.

Uprichard and her colleagues showed that knocking down or blocking access to the NPC1L1 receptor prevented the virus from entering and infecting cells.

Bruno Sainz Jr., postdoctoral research associate in medicine and first author of the paper, said the receptor has been well studied because of its role in cholesterol metabolism.

The FDA-approved drug ezetimibe, sold under the trade name Zetia to lower cholesterol levels, is perfectly targeted to the receptor, Sainz said, giving the researchers an ideal way to test the receptor’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.

The researchers showed that ezetimibe inhibited HCV infection in cell culture and in mice transplanted with human liver cells. And, unlike other available treatments for HCV, ezetimibe inhibited infection by all six types of the virus.

The study opens up a number of possibilities for therapeutics, Uprichard said.

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, she said.

While current drugs are highly toxic and often cannot be tolerated by transplant patients taking immunosuppressant drugs, ezetimibe has been used safely 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 foresee 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.”

The study was funded 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.

Other contributors to the study include 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.


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