By wu chao
A molecule embedded in the membrane of human liver cells that aidsin cholesterol absorption also allows the entry of hepatitis C virus, the first step in hepatitis C infection, according toresearch at the University of Illinois at Chicago College ofMedicine. The cholesterol receptor offers a promising new target foranti-viral therapy, for which an approved drug may already exist,say the researchers, whose findings were reported online in advanceof publication in Nature Medicine. An estimated 4.1 million Americans are infected with hepatitis Cvirus, or HCV, which attacks the liver and leads to inflammation,according to the National Institutes of Health. Most people have nosymptoms initially and may not know they have the infection untilliver damage shows up decades later during routine medical tests. Previous studies showed that cholesterol was somehow involved inHCV infection.
The UIC researchers suspected that a receptor calledNPC1L1, known to help maintain cholesterol balance might also betransporting the virus into the cell. The receptor is common in the gut of many species – but is found onliver cells only in humans and chimpanzees, says Susan Uprichard,assistant professor in medicine and microbiology and immunology andprincipal investigator in the study. These primates, she said, arethe only animals that can be infected by HCV. Uprichard and her coworkers showed that knocking down or blockingaccess to the NPC1L1 receptor prevented the virus from entering andinfecting cells.
Bruno Sainz, Jr., UIC postdoctoral research associate in medicineand first author of the paper, said because the receptor isinvolved in cholesterol metabolism it was already well-studied. Adrug that “specifically and uniquely targets NPC1L1” already existsand is approved for use to lower cholesterol levels, he said. The FDA-approved drug ezetimibe (sold under the trade-name Zetia)is readily available and perfectly targeted to the receptor, Sainzsaid, so the researchers had an ideal method for testing NPC1L1’sinvolvement in HCV infection. They used the drug to block the receptor before, during and afterinoculation with the virus, in cell culture and in a small-animalmodel, to evaluate the receptor’s role in infection and the drug’spotential as an anti-hepatitis agent.
The researchers showed that ezetimibe inhibited HCV infection incell culture and in mice transplanted with human liver cells. And,unlike any currently available drugs, ezetimibe was able to inhibitinfection by all six types of HCV. The study, Uprichard said, opens up a number of possibilities fortherapeutics. Hepatitis C is the leading cause for liver transplantation in theU.S., but infected patients have problems after transplant becausethe virus attacks the new liver, Uprichard said. While current drugs are highly toxic and often cannot be toleratedby transplant patients taking immunosuppressant drugs, ezetimibe isquite safe and has been used long-term without harm by people tocontrol their cholesterol, Uprichard said.
Because it preventsentry of the virus into cells, ezetimibe may help protect the newliver from infection. For patients with chronic hepatitis C, ezetimibe may be able to beused in combination with current drugs. “We forsee future HCV therapy as a drug-cocktail approach, likethat used against AIDS ,” Uprichard said. “Based on cell culture and mouse model data, weexpect ezetimibe, an entry inhibitor, may have tremendous synergywith current anti-HCV drugs resulting in an improvement in theeffectiveness of treatment.” Additional References Citations.
