The innate immune system is our first line of defense against pathogenic challenge. These responses include cell-intrinsic mechanisms to combat these invaders in infected cells. Autophagy, the mechanism by which cells engulf cytoplasmic components, has been shown to have antimicrobial properties against intracellular bacteria. This process leads to the destruction of these cytoplasmic microorganisms. It has been proposed that such a mechanism may play an important role in controlling viral infection. Our preliminary data support this in that loss of this conserved pathway leads to an increase in viral replication in Drosophila. This suggests that autophagy plays an important antiviral role. In this proposal we seek to establish the mechanism by which the autophagic pathway affects viral propagation and pathogenesis, and the mechanisms whereby this process is activated to clear the viral invader. By taking advantage of the powerful tools available in this model system, including genetics and functional genomics, to investigate these questions in a variety of contexts we will be uniquely situated to identify conserved intrinsic mechanisms by which all organisms fight viruses. The identification of new host factors amenable to inhibition may lead to targets for much-needed antiviral therapeutics.