Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.

Adviser: Peter Cresswell.

The anti-viral protein, viperin, is an interferon stimulated gene highly upregulated upon viral infections. Although it has been found to be important in defence against multiple different viruses, the diversity between its proposed mechanisms, ranging from signalling effects to lipid metabolism, suggests that it is far from being fully understood. Nonetheless, it can be agreed upon that viperin plays an important role in RNA virus infections, particularly that of flaviviruses. In line with this, another key player in cellular responses to RNA viruses is MAVS, an adaptor protein bridging the cytoplasmic viral RNA receptors MDA5 and RIG-I with downstream signalling factors leading to the activation of the transcription factors NF-&kgr;B, IRF3, and IRF7. As detailed in this dissertation, investigations into these two proteins led to the discovery that they interact, and further to the identification of residues that are important for this interaction. Mitochondria-associated ER membranes are the most likely site for their interaction, given that both can be found there, independently of one another. Functionally, it appears that viperin acts as a negative regulator of MAVS-mediated IFNbeta production, particularly upon MDA5 activation. Under basal conditions, only a small amount of viperin is present in the cell. Upon binding of RNA ligands to the receptors MDA5 and RIG-I, MAVSmediated signalling is activated and leads to the expression of anti-viral and pro-inflammatory genes, including viperin. Six to eight hours after infection, viperin, now highly expressed, would hypothetically tip the balance in the other direction, shutting off the response and acting as part of a negative feedback mechanism, preventing pathology from excessive inflammation. How exactly viperin mediates this inhibition is unknown. However, the observation that mutants less capable of binding to MAVS are better inhibitors suggests that the inhibitory mechanism of viperin may not directly involve MAVS, meaning that it could function via a separate unknown pathway to inhibit IFNbeta production. The interaction between viperin and MAVS could hypothetically sequester viperin until a high expression level later in the infection overwhelms the sequestration. This would explain why interaction mutants of viperin cause even more IFM3 inhibition, since MAVS is less able to lock them down.

This dissertation describes a novel interaction between viperin and MAVS, and by exploring the relationship between the two proteins, a role for viperin as a negative regulator of a central anti-viral pathway. This could lead to potential therapeutic applications, particularly since RNA viruses such as Chikungunya, Dengue, and West Nile impact many people around the world each year.