The battle for the 5' end: dissecting a novel virus-specific translation mechanism driven by eIF3

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Our aim is to understand a new mechanism of protein production by viruses of clinical and economical importance and examine how it contributes to escaping detection from the host. Cells within the body respond to external stimuli in many ways, the most common of which is via the regulation of gene expression. In response to external stresses such as infection, cells can pause protein synthesis, or translation, and thus the decoding of genetic information. This defense mechanism allows cells to survive by limiting the use of energy and nutrients that protein synthesis requires until the stress is resolved. It also blocks the spread of viruses as viruses are dependent on host cell resources to produce viral proteins and replicate. Because of this, viruses have developed strategies to produce their proteins using alternative mechanisms. Using different viruses as models, we have previously made significant advances in identifying new mechanisms that viruses use to manipulate the host cell by regulating translation. Viruses transmitted by mosquitoes represent a major burden on human and animal health. Among these, dengue virus is a prominent human health threat causing millions of infections every year worldwide, with no broadly effective or specific treatment. We previously showed that dengue virus infection results in a block in host protein synthesis, yet it remains a mystery how viral proteins are translated to support viral propagation. This is important because understanding how viruses hijack host resources can reveal a new Achilles' heel in the viral armour.Based on our results, we propose that dengue virus proteins are translated via a novel mechanism that uses a known cellular translation factor, eIF3, in a non-conventional manner to mediate translation. We also propose that this mechanism could help dengue virus escape detection by the host. Therefore, our objectives are to 1- characterize how eIF3 interacts with the viral RNA; 2- elucidate how this contributes to a new mechanism of translation and 3- establish how this mechanism competes with non-self detection of the viral RNA by the host. From this work we expect to advance our knowledge of how viruses take control of host resources to ensure viral proteins are made. This mechanism is novel, and we think it represents a new line of counterdefence evolved by viruses. Therefore, it can help identify new ways to inhibit virus replication and develop novel antiviral therapies for an important group of viruses. Understanding the fundamental mechanisms of gene regulation is important for virologists, but also for broader academic communities. It may also help us to appreciate better a basis of several pathologies, such as cancer or neurodegenerative diseases, that are linked to alternative translation mechanisms.