During viral replication, defective genomes may arise that lack essential sequences. These so-called defective genomes cannot replicate unless they are in the same cell as a helper virus. Defective genomes play a role in modulating pathogenesis of respiratory syncytial virus in humans.
Copy-back defective viral genomes (cbDVGs) of RSV arise when the viral RNA polymerase halts and then turns around and begins copying the nascent strand (illustrated below – image credit). Because the cbDVGs have strands of both (+) and (-) polarity it is possible to design primers to amplify them by RT-PCR.
It has been suspected that defective viral genomes might modulate viral pathogenesis because they are efficient inducers of interferon. In a study of 122 hospitalized pediatric patients with RSV infection, the presence of cbDVGs was associated with higher viral loads and longer hospitalizations. Furthermore, patients harboring cbDVGs had higher expression of pro-inflammatory cytokine genes.
Unexpectedly, non-hospitalized patients with confirmed RSV infection also had high levels of cbDVGs and high viral loads. Analysis of the kinetics of cbDVG production revealed that when cbDVGs arise early in infection, less severe symptoms present. In contrast, when cbDVGs arise later in infection, higher viral loads and more severe disease occur. The latter patients also produce higher levels of pro-inflammatory cytokines which likely cause immunopathogenesis.
An interpretation of these findings is that when cbDVGs arise early in infection, they induce antiviral immune responses that limit viral replication and disease. When cbDVGs arise later, the virus has already reproduced to high levels, leading to more severe disease. The factors that regulate cbDVGs production are not known, but could involve sex, age, immune status, and the levels of the defective genomes in the virus inoculum.
These results are of interest because it has not been possible to predict which RSV infected patients will develop severe disease. It might be possible to use levels of cbDVGs to forecast clinical outcome.
When defective viral particles were discovered many years ago, Alice Huang proposed that they might modulate viral pathogenesis. It was not until the 1990s that the technology became available to test this hypothesis. The results with RSV suggest that whether cbDVGs are beneficial or detrimental depends on when they arise in infection.