Despite the fact that it was eradicated thanks to vaccination, smallpox continues to cause considerable concern in the fight against bioterrorism and emerging diseases. Other viruses of the same family, the poxviruses, can be transmitted to humans and vaccination has serious side effects.
Moreover, strains of smallpox are currently stored in the United States and Russia. Developing new antiviral molecules requires prior understanding of how the virus spreads in the body, and consequently, its virulence.
The researchers at CEA-IBITECS and their partners from the University of Edinburgh have studied some actors of viral replication involved in the entry of proteins into cells and their transport via vesicles. They focused their attention on the GARP
[1] complex, an essential component of a pathway through which these vesicles travel from the cell membrane to the Golgi apparatus, where the proteins are modified. In which way is it involved in viral replication?
The scientists used the vaccinia virus as a model for the smallpox virus. To understand the role of GARP, the biologists used Si-RNAs to cause it to act dysfunctionally. In the absence of an operational GARP complex, it appears that the recycling of two viral proteins necessary for the formation of the virions with a threefold envelope, the most virulent form of virions and responsible for the spread of the virus in the organism, is blocked.
In addition, the researchers tested the importance of GARP in viral replication using retro-molecules discovered in their laboratory, which inhibit vesicle transport and therefore also prevent the normal functioning of GARP. These are Retro-1 and Retro-2, tested in vitro and in a mouse model, respectively. In the same way as the Si-RNAs, these transport inhibitors block the formation of the threefold-envelope virions of the vaccinia virus in vitro. Lastly, Retro-2 reduces the symptoms and stops the mortality in mice infected with vaccinia.
Retro-2 had already been proven effective to fight ricin and Shiga toxins in human cells and in intoxication models in mice.
These results, which outline the involvement of the GARP complex in the morphogenesis of the vaccinia virus, pave the way for the development of new antivirals against poxviruses and smallpox. This work was financed by the French interdepartmental R&D program against the NRBCE risks (Nuclear, Radiological, Biological, Chemical, Explosives).
[1] Golgi-Associated Retrograde Pathway complex