Cells sense danger by detecting molecules that are normally absent. Double-stranded RNA (dsRNA) is considered a hallmark of viral infection. RNA viruses generate dsRNA during genome replication, while DNA viruses may generate dsRNA through symmetrical transcription from both genomic strands, despite little direct evidence. Nonetheless, DNA viruses inhibit cellular dsRNA sensors, and viral mutants lacking inhibitors activate dsRNA sensors. More recently, dsRNA sensor activation was shown to induce formation of cytoplasmic ribonucleoprotein (RNP) granules that purportedly strengthen cellular antiviral responses, yet the mechanisms governing granule formation and function are controversial. This thesis aims to address two key questions at the intersection of DNA viral infection and cellular RNA sensing, using infection of human cells with the prototypical, nuclear-replicating DNA virus human adenovirus (Ad): 1) How do DNA viruses regulate complex transcriptomes to prevent dsRNA formation? 2) Do infection-induced RNP granules differ from those formed upon non-physiologic chemical stress?First, we use multiple genetic, biochemical, and sequencing approaches to investigate dsRNA formation during Ad infection. We hypothesize dsRNA should only form if viral mRNAs are inefficiently processed. Indeed, only splicing-defective mutants produced dsRNA. Here, we reveal a novel mechanism whereby adenovirus prevents immunostimulatory dsRNA formation by targeting specific cellular splicing proteins that would otherwise impair viral RNA splicing. Second, we explore the properties of RNP granules during DNA viral infection. We identify adenoviral mutants that trigger formation of related, but distinct RNP granules—stress granules (SGs) and RNase L-dependent Bodies (RLBs)—and use infection with these mutants to compare granule properties to those formed upon field-standard chemical stressors. Our immunofluorescence data reveal differences in the composition, and potentially function, of granules induced by viral or non-viral stressors. Additionally, we reveal Ad infection blocks SG formation by non-viral stressors. Collectively, our studies shed light on the intricate control DNA viruses exert on host RNA processing and sensing machinery and may enable novel therapies targeting this critical virus-host interface.