When DGAT1 is inhibited or missing, viral-particle assembly is prevented.
Scientists at the Gladstone Institute of Virology and Immunology (GIVI) have found that the enzyme DGAT1, associated with the storage of fat in the liver, is required for the infectious activity of HCV. “Our results reveal a potential Achilles heel for HCV infection,” says Melanie Ott, M.D., Ph.D., senior author on the paper, which appears in Nature Medicine. “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 life cycle 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 bloodstream to infect more cells. These processes were thought to occur at specialized membranes inside the cell.
Recently, however, it has been shown that fat droplets are critically involved. DGAT1 is one of the enzymes that help to form fat droplets. The Gladstone team, led by Eva Herker, Ph.D., 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,” says Dr. Herker. “We found that HCV specifically relies on one DGAT enzyme, 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 then sought to identify which step in the HCV life cycle 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.