Most viruses of clinical relevance encode antagonists that interfere with the type I interferon (IFN) pathway thus promoting the establishment of the infection and pathology. The mechanisms involved in initiating the antiviral immune response in the presence of antagonists of the type I IFN pathway have not been identified. These mechanisms may represent novel targets to minimize pathology and/or may explain different clinical outcomes to common viral pathogens. Our group established that special defective forms of viral genomes (DVGs), which were until recently considered an epiphenomenon of in vitro virus replication, are potent danger signals that trigger the host response, even in the presence of virus-encoded antagonists. Moreover, we demonstrated that natural accumulation of DVGs in the lung during infection with the mouse respiratory pathogen Sendai virus (SeV) or with mouse-adapted influenza A virus (IAV) correlated with the onset of the antiviral response, and that production of the primary antiviral cytokine IFN beta was limited to the DVG-positive lung cellular fraction. Importantly, analysis of respiratory secretions from children infected with the SeV-related human respiratory syncytial virus (RSV) demonstrated that detection of DVGs is also associated with enhanced expression of transcripts for type I IFNs in humans. Notably, DVGs have been identified in the serum of patients infected with a variety of viruses and our data are the first demonstration that DVGs generated during an acute infection promote the onset of the immune response in vivo. We thus hypothesize that DVGs are essential for the induction of the antiviral response in infections with viruses that block the type I IFN pathway and that their presence determines the clinical outcome of the infection. The goals of this renewal application are (i) to identify unique molecular mechanisms governing the strong immunostimulatory ability of DVGs, (ii) to determine how do DVGs initiate the immune response in vivo, and (iii) to evaluate the role of RSV DVGs in the virus pathogenesis in the human lung. Overall, these studies will advance our understanding of the mechanisms involved in the onset of the innate immune response to virus infection and may have a significant impact on the development of novel antiviral treatments and prognostic tools.