Molecular characterization of arenavirus defective viral genomes reveals sequence features associated with their formation

Infection with diverse RNA viruses can generate defective viral genomes (DVGs) that, while unable to support productive virus infection on their own, appear to play a crucial role in determining infection outcome. In light of this apparent biological importance, there is an urgent need to better understand the sequence characteristics of individual DVGs and the molecular mechanisms that regulate their formation to study their biological functions. We have now characterized several DVGs that are highly enriched during infection with the arenavirus Tacaribe virus. Functional analysis of a subset of these DVGs showed length-dependent competition for the viral RNA synthesis machinery, while detailed sequence analysis revealed that DVG formation involves either regions of sequence identity within the genome or the presence of specific nucleotide sequences. Understanding these mechanisms opens up the possibility to leverage DVG generation in support of antiviral and/or vaccine attenuation approaches.