Researchers at University of Pennsylvania School of Veterinary Medicine have found out a protein called with antiviral activity, which is capable in inhibiting the Ebola virus budding.
This observation could describe the mechanism by which ISG15 successfully inhibits other viruses, including HIV-1 and herpes simplex virus type I.
This study, led by Ronald Harty, associate professor in the Department of Pathobiology at Penn Vet, shows for the first time how ISG15 slows the spread of Ebola virus budding. The findings of this study may provide implications of treatments for Ebola outbreaks that now prove fatal for as many as 90 percent of victims.
The researchers said that ISG15 indirectly inhibits budding - by inhibiting the host cell protein Nedd4, used by the viral protein VP40 to escape from cells and allow for virus spread.
"Inhibit the proteins used by a virus to reproduce and you are inhibiting the virus itself. Without host Nedd4, the Ebola virus still buds and attacks, but it doesn't bud as well. The long-term goal of our research is to understand the interplay between host and virus, with the hope of creating an anti-viral drug or inhibitor, much like how Tamiflu doesn't cure the flu but slows down the viral process. The drug would be designed to dampen or slow down viral budding to allow an infected person's immune system to fight back," said Harty.
The Ebola virus VP40 protein plays a pivotal role in the process of virus assembly and release from infected cells. VP40 buds from mammalian cells independent of other viral proteins, and efficient release of VP40 virus-like particles, VLPs, requires interactions with host proteins such as tsg101 and Nedd4, an E3 ubiquitin ligase. Ubiquitin itself is believed to be exploited by Ebola virus for efficient virus outlet.
It was shown in the study that expression of free ISG15, or the ISGylation System, UbE1L and UbcH8, inhibits budding of Ebola virus VP40 VLPs.
The researchers focussed on the molecular mechanism of this inhibition, and showed that ISG15 cooperates with Nedd4 ubiquitin ligase and inhibits ubiquitination of VP40, thus blocking budding of VP40 VLPs.
These findings provide evidence of antiviral activity of ISG15 against Ebola virus and propose a plan of action involving disruption of Nedd4 function and subsequent ubiquitination of VP40.
This study has extended the team's knowledge of the reproductive process of Ebola and other viruses with similar reproductive mechanisms.
The findings of this study are reported in the current issue of the Proceedings of the National Academy of Sciences.