October 12, 2010

Am J Gastroenterol advance online publication 5 October 2010; doi: 10.1038/ajg.2010.370

Paul J Clark MD 1, Alex J Thompson MD, PhD 1 and John G McHutchison MD 1

1 Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, School of Medicine, Duke University, Durham, North Carolina, USA

Correspondence: Paul J. Clark, MD, Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, PO Box 17969, Durham, North Carolina 27715, USA. E-mail: paul.clark@duke.edu

Received 5 April 2010; Accepted 16 August 2010; Published online 5 October 2010.

Abstract

Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). These important new studies are reviewed and their future clinical implications discussed. Single-nucleotide polymorphisms in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-λ-3 or IL28B gene, are strongly associated with treatment response to pegylated IFN and ribavirin in patients infected with genotype 1 HCV. The good response variant is associated with a twofold increase in the rate of cure. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV. The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type.

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Public release date: 10-Oct-2010

Contact: Valerie Tucker
vtucker@gladstone.ucsf.edu
415-734-2019
Gladstone Institutes

Discovery points to a potential new strategy for treating the disease

SAN FRANCISCO, CA—October 10, 2010—Scientists at the Gladstone Institute of Virology and Immunology (GIVI) have found that an enzyme associated with the storage of fat in the liver is required for the infectious activity of the hepatitis C virus (HCV). This discovery may offer a new strategy for treating the infection.

More than 160 million people are infected throughout the world, and no vaccine is available to prevent further spread of the disease. Current treatments are not effective against the most common strains in the US and Europe. The study, published in the journal Nature Medicine, shows that the enzyme DGAT1 is a key factor in HCV infection. With several potential DGAT1 inhibitors already in the drug-development pipeline, a treatment for HCV may be possible in the near future.

"Our results reveal a potential 'Achilles heel' for HCV infection," said Melanie Ott, MD, PhD, senior author on the study. "Several DGAT1 inhibitors are already in early clinical trials to treat obesity-associated diseases. They might also work against HCV."

At first glance, the HCV lifecycle is fairly simple. The virus enters the cell. One large protein is produced and cut into several smaller viral enzymes and proteins that build the virus. The RNA genome is copied, and the new RNAs and structural proteins are used to make new virus particles that are released into the blood stream for to infect more cells. These processes were thought to occur at specialized membranes inside the cell. However, recently it has been shown that fat droplets are critically involved.

Fat droplets, which store fat in cells, have become a hot new topic in biology. DGAT1 is one of the enzymes that help to form fat droplets. The Gladstone team, led by Eva Herker, PhD, discovered that HCV infection and viral particle production are severely impaired in liver cells that lack DGAT1 activity.

"DGAT enzymes produce the fat that is stored in the droplets that are important for HCV replication, so we wondered if inhibiting those enzymes might disrupt the viral life cycle," said Dr. Herker. "We found that HCV specifically relies on one DGAT enzymes, DGAT1. When we inhibit DGAT1 with a drug, the liver still produces fat droplets through another DGAT enzyme but these droplets cannot be used by HCV."

The team sought to identify which step in the HCV lifecycle requires DGAT1. They found that DGAT1 interacts with one viral protein, the viral nucleocapsid core protein, required for viral particle assembly. The core protein normally associates with the surface of fat droplets but cannot do so when DGAT1 is inhibited or missing in infected cells.

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Researchers at Gladstone Institute of Cardiovascular Disease had previously cloned DGAT1.

Charles Harris, Robert V. Farese, Jr. and Katrin Kaehlcke were part of the Gladstone team. Celine Hernadez, Arnaud Charpentier and Arielle Rosenberg supported the research from the Universite Paris Descartes.

This work was supported by funds from the Gladstone Institutes, the Hellman Family Foundation, the US National Institutes of Health and the UCSF Liver Center. Additional support was provided through fellowships from the Human Frontiers Science Program, the Agence nationale de recherches sur le sida et les hépatites virales, and a training grant from the National Institute of Diabetes and Digestive and Kidney Diseases.

Melanie Ott's primary affiliation is with the Gladstone Institute of Virology and Immunology, where she is associate investigator and where her laboratory is located and her research is conducted. She is also an associate professor of medicine at UCSF.

Gladstone Institutes is a nonprofit, independent research and educational institution, consisting of the Gladstone Institute of Cardiovascular Disease, the Gladstone Institute of Virology and Immunology, and the Gladstone Institute of Neurological Disease. Independent in its governance, finances and research programs, Gladstone shares a close affiliation with UCSF through its faculty, who hold joint UCSF appointments.

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