Immunostimulatory Defective Viral Genomes from Respiratory Syncytial Virus Promote a Strong Innate Antiviral Response during Infection in Mice and Humans

Abstract

Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.

Reduced accumulation of defective viral genomes contributes to severe outcome in influenza virus infected patients

“…Although DVGs have been described in natural animal infections [33, 34] and in pandemic AH1N1pdm09- and other respiratory virus-infected individuals [35, 36] their role in viral pathogenicity in patients has not been evaluated. The correlation between DVGs accumulation and severe disease observed in the severe/fatal- and mild-case viruses isolated from respiratory samples suggests that DVGs generation is a critical feature of severe influenza virus infection.…”

Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro : Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase

“…Persistent infections by RNA viruses such as measles virus, human parainfluenza virus, SeV, and dengue virus have been associated with the development of DIPs or DVGs (14,24,41). DIPs are usually produced during viral replication at a high MOI in vitro and lack essential genes to sustain viral replication in the absence of a helper virus (42).…”

“…For establishment of persistent infection in vitro, there is normally a fine dynamic equilibrium between virus infection and viral clearance by host innate immune responses. Viruses isolated from persistently infected (PI) cells have genomic mutations leading to the generation of temperature-sensitive mutants or defective interfering particles (DIPs) (also termed defective viral genomes [DVGs]), as shown for Sendai virus (23), measles virus (14), and RSV (24). The PI cells display some of the following phenotypes: reduced viral release (21), resistance to superinfection (25), and resistance to exogenous IFN (26).…”

Respiratory syncytial virus infection: an innate perspective

“…UV-inactivated RSV does not elicit type I IFN responses 24, 52 , but defective RSV genomes can in both mice and humans 53 . Interestingly, the major sources of type I IFNs in the lower airways of mice during experimental RSV infection are AMs 24 , and they use cytosolic MAVS-coupled sensors to induce this production 24, 52 .…”