Abstract

Small RNA viruses have limited genetic information and therefore many of the virally encoded proteins have multiple functions. As part of their genetic repertoire, most small RNA viruses also have to produce specific antagonists of the interferon (IFN) system that, whilst not essential for virus replication, are nevertheless absolutely necessary for virus pathogenesis and survival in nature. Many of these viral IFN antagonists are therefore multifunctional proteins with other roles in the replication cycle of the virus. Furthermore, the way in which viruses interact with the IFN system may play an important role in defining the type of disease they induce and even their epidemiology. This principle will be illustrated using examples from our work on the NS1 protein of influenza virus and the V protein of parainfluenza virus type 5 (PIV 5). For example, the NS1 protein intercedes at multiple points within the cells anti-viral defence responses, including binding dsRNA, inhibiting RIG -I and PKR as well as preventing the correct maturation and export of cellular mRNAs from the nucleus to the cytoplasm. In addition to these inhibitory actions on cellular processes, NS1 also specifically activates cellular PI3 kinase, although the biological consequences for this remain unclear. With regards the V protein of PIV5 , this protein acts as an IFN antagonist by both limiting the production of IFN and blocking IFN signalling. The V protein at least partially inhibits IFN production by binding to mda-5, an intracellular detector of viruses, and inhibiting its ability to activate the intracellular signalling c yetascade that leads to the production of IFN -β. To block IFN signalling, the V protein specifically targets the cellular transcription factor STAT1 (which is essential for IFN signalling) for proteosome-mediated degradation. In addition, the V protein also activates AKT and binds to soluble forms of the nucleocapsid protein and thus has important roles to play in controlling transcription and replication of the virus genome. Thus, by further understanding the structure/multifunctional nature of these small IFN antagonists a better understanding of the molecular pathogenesis of these viruses will be achieved and improved mechanisms for their control may be developed through the design of virus vaccines and development of novel anti-viral drugs.