Diacylglycerol Acyltransferase-1 (DGAT1) Localizes Hepatitis C Virus NS5A Protein to Lipid Droplets and Enhances NS5A Interaction with the Viral Capsid Core

More than 170 million people worldwide are infected with Hepatitis C Virus (HCV).  Persistent viral replication in patients fuels viral transmission and the risk of progressive liver diseases, including cirrhosis and hepatocellular carcinoma.  Currently, there is no vaccine and the treatment regimens remain ineffective. HCV is a positive, single-stranded RNA virus of the Flaviviridae family which encodes a single polyprotein that is proteolytically processed into 10 functional HCV proteins – the structural Core, E1 and E2 proteins and the non-structural NS2, NS3, NS4A, NS4B, NS5A, NS5B and p7. After the discovery of an infectious cell culture system for HCV, cellular lipid droplets (LDs) have rapidly emerged as important viral assembly sites.  Research in the Ott lab has focused on mechanistic insights into how HCV accesses LDs and previously reported that the HCV Core protein interacts with the cellular Diacylglycerol Acyltransferase-1 (DGAT1) , but not its sister enzyme, DGAT2. Recently Camus et. al. reported a new interaction between the non-structural protein NS5A and DGAT1, and showed that the trafficking of NS5A to LDs depends on DGAT1 activity. DGAT1 forms a complex with NS5A and Core and facilitates the interaction between both viral proteins.  These data suggest a model where DGAT1 serves as a cellular “hub” for HCV Core and NS5A proteins, guiding both onto the surface of the same subset of LDs to accomplish virus assembly. These results highlight the critical role of DGAT1 as a host factor for HCV infection and as a potential drug target for antiviral therapy.  

Discovery of Snake Arenaviruses

For many years, a mysterious disease in boa constrictors and pythons called Inclusion Body Disease (IBD) has been the scourge of aquariums, breeders, and pet snake owners - and of course the snakes themselves. The disease is ultimately fatal, and until now, its cause was unknown. Using the latest methods in ultra deep sequencing and de novo sequence assembly, Mark Stenglein and co-authors at the DeRisi lab at UC San Francisco, in collaboration with the California Academy of Science and local veterinarians, have identified a novel snake arenavirus that is closely linked to the disease.  The newly discovered virus is only distantly related to previously described arenaviruses and contains a combination of arenavirus and filovirus genes.  (Notably, while filoviruses include the infamous Ebola, the snake virus has never been seen to infect humans).

Current research in this project extends in two directions: first, broadening our knowledge of snake and reptilian viruses using the snake arenavirus as a foothold; and second, fulfilling Koch’s postulates for the snake arenavirus, thus aiming to establish it as the causative agent of IBD.

The paper describing this discovery is published in ASM's new open-access journal mBio.