This technology includes a novel minigenome assay for arenaviruses that allows for high-throughput screening (HTS) of potential antiviral compounds. To complement to minigenome assay, we have also developed a technique to generate recombinant arenaviruses expressing a reporter protein to allow to HTS of antiviral compounds at BSL-4. This allows for confirmation of potential hits identified by the initial minigenome screen. Human infections with some Arenaviruses such as Lassa (LASV) and Junin (JUNV) virus can result in viral hemorrhagic fever (VHF) disease. LASV in particular is an important global health issues resulting in significant morbidity and mortality, but treatment options remain limited. A major factor impeding the development of antiviral compounds to treat these infections is the need to manipulate the virus under BSL-4 containment, limiting research to a few institutes worldwide.