Defective viral genomes determine respiratory syncytial virus disease severity in children and adults

Respiratory syncytial virus (RSV) is an important cause for respiratory illness in children, immunosuppressed adults, and elderly. The outcomes of RSV vary, ranging from no symptoms, mild cold like symptoms, bronchiolitis, wheezing, and even death. Factors determining the disease severity are largely unknown. In this study, we propose copy-back DVGs (cbDVGs) are an additional viral factor that impacts RSV disease severity. cbDVGs are the truncated forms of viral genomes generated during viral replication and they suppress the standard viral replication by directly competing viral machinery and stimulating antiviral responses. Here we correlate the disease severity and viral load with the presence of cbDVGs in RSV-infected individuals from a longitudinal adult cohorts. Healthy adults were inoculated with 10^4 pfu RSV A MEMPHIS strain and were followed for up to 6 months. Nasal washes, symptom scores, and blood were taken daily for the first two weeks. We found that cbDVGs alter the RSV disease severity depending on when and how long they are present in infected individuals. cbDVGs appeared earlier are correlated with less viral loads and milder diseases. cbDVGs that appear later, especially the ones present for prolonged periods of time, fail to control the virus and are accompanied with inflammatory immune responses and worse symptom scores. Taken together, our cohort studies demonstrate that the kinetics of cbDVG appearance and the length of presence impact RSV disease severity.