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.
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.
Valerie Tucker | EurekAlert!
Atomic-level motion may drive bacteria's ability to evade immune system defenses
24.04.2017 | Indiana University
Two-dimensional melting of hard spheres experimentally unravelled after 60 years
24.04.2017 | University of Oxford
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
24.04.2017 | Physics and Astronomy
24.04.2017 | Materials Sciences
24.04.2017 | Life Sciences