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CURATOR
A pinboard by
Keaton Crosse

PhD Student, La Trobe University

PINBOARD SUMMARY

Characterising and utilising the immuno-modulatory capabilities of Viperin

Viperin is a unique and highly evolutionarily conserved protein that is able to restrict many diverse viruses. As a prominent member of our early innate immune system, viperin utilises multiple mechanisms to fight off viral invaders. Of these mechanisms, many involve the protein’s direct interaction and inhibition of viruses such as Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV), but more recently have involved an indirect mode of viral inhibition.

My research focuses on these indirect mechanisms of viperin’s restriction of viruses. For the first time I have been able to show that viperin achieves its inhibition of a collection of viruses by interacting with key immune molecules. Acting a sort of scaffold, viperin pulls together these key immune molecules to aid their signalling activation which leads to an enhanced transduction of the immune signal. In doing this viperin has been shown to increase the production of the potent anti-viral cytokine, interferon beta, and upregulate other anti-viral proteins. Not only does this action help us to eliminate viruses that have already infiltrated our cells, but it also primes neighbouring uninfected cells to more effectively fight off viruses.

The next stage of my research will involve delivering recombinant viperin protein into an infection model to determine its use as an alternative anti-viral therapeutic agent against a wide range of viruses. The need for such alternative anti-viral treatments has never been greater with the high prevalence of emergent viral diseases, such as Zika, Ebola and Swine Flu to which we have no treatment. Viperin’s potential application as a potent anti-viral treatment offers promise as an effective pan-viral treatment that does not have the high costs or long development time associated with typical vaccine development. In addition to this, due to its action on the patient and not the virus, this therapeutic approach is less susceptible to the generation of viral resistance. My research highlights the necessity of better understanding the intricate and complex actions of our immune system to develop better treatments against viral diseases.

4 ITEMS PINNED

Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin.

Abstract: The host protein viperin is an interferon stimulated gene (ISG) that is up-regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid-inducible gene I (RIG-I). Viperin did not inhibit DENV-2 entry but DENV-2 RNA and infectious virus release was inhibited in viperin expressing cells. Conversely, DENV-2 replicated to higher tires earlier in viperin shRNA expressing cells. The anti-DENV effect of viperin was mediated by residues within the C-terminal 17 amino acids of viperin and did not require the N-terminal residues, including the helix domain, leucine zipper and S-adenosylmethionine (SAM) motifs known to be involved in viperin intracellular membrane association. Viperin showed co-localisation with lipid droplet markers, and was co-localised and interacted with DENV-2 capsid (CA), NS3 and viral RNA. The ability of viperin to interact with DENV-2 NS3 was associated with its anti-viral activity, while co-localisation of viperin with lipid droplets was not. Thus, DENV-2 infection induces viperin which has anti-viral properties residing in the C-terminal region of the protein that act to restrict early DENV-2 RNA production/accumulation, potentially via interaction of viperin with DENV-2 NS3 and replication complexes. These anti-DENV-2 actions of viperin show both contrasts and similarities with other described anti-viral mechanisms of viperin action and highlight the diverse nature of this unique anti-viral host protein.

Pub.: 03 May '13, Pinned: 31 Jul '17