The Rift Valley fever virus (RVFV) is responsible for numerous, explosive epizootics throughout Africa and the Arabian Peninsula. The virus causes disease predominantly in humans and livestock, with sheep and cattle being particularly susceptible.In humans, the disease generally manifests as a flu-like illness; however, in a small percentage of cases, severe symptoms develop, such as encephalitis and hemorrhagic fever disease.In these severe cases, mortality rates are high. Livestock often succumb to the viral infection, and case-fatality rates are particularly high among young animals.Outbreaks are devastating to the public health and regional economies, and the development of antiviral therapies is difficult due to the limited understanding of the RVFV replicative cycle.We have developed a system for the generation of Rift Valley fever virus-like particles (RVF-VLPs).The RVF-VLPs are antigenically and morphologically indistinguishable from virulent RVFV virus, but can only perform a single round of infection.Using the virus-like particle system for RVFV, in combination with biochemical and crystallization techniques, we have elucidated the roles of the viral proteins in multiple steps of the viral replicative cycle.Specifically, we describe crucial interactions necessary for replication and transcription, elucidate the structure of the nucleocapsid protein, identify the envelope glycoprotein, Gn, as necessary and sufficient for the recruitment and packaging of the RdRp and encapsidated genome into virus particles, determine that the encapsidated genome triggers the efficient release of virus, and ascertain the limitations governing RVFV reassortment with other phleboviruses.Based on our results, we suggest targets for the development of therapeutics directed against RVFV and other phleboviruses.
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