Abstract
Replication defective viral genomes (DVGs) generated during virus replication are the primary triggers of antiviral immunity in many RNA virus infections. However, DVGs can also facilitate viral persistence. Why and how these two opposing functions of DVGs are achieved remain unknown. Here we report that during Sendai and respiratory syncytial virus infections DVGs selectively protect a subpopulation of cells from death, thereby promoting the establishment of persistent infections. We find that during Sendai virus infection this phenotype results from DVGs stimulating a mitochondrial antiviral-signaling (MAVS)-mediated TNF response that drives apoptosis of highly infected cells while extending the survival of cells enriched in DVGs. The pro-survival effect of TNF depends on the activity of the TNFR2/TRAF1 pathway that is regulated by MAVS signaling. These results identify TNF as a pivotal factor in determining cell fate during a viral infection and delineate a MAVS/TNFR2-mediated mechanism that drives the persistence of otherwise acute viruses.
Highlights
Replication defective viral genomes (DVGs) generated during virus replication are the primary triggers of antiviral immunity in many RNA virus infections
Using fluorescent in situ hybridization targeting ribonucleic acid molecules (RNA FISH) to distinguish DVGs from standard viral genomes during infection, we reveal that during infection with the murine parainfluenza virus Sendai (SeV) or respiratory syncytial virus (RSV) DVGs accumulate only in a subpopulation of infected cells, and that these cells survive the infection longer than cells enriched in full-length virus Survival of DVG-high cells is dependent on mitochondrial antiviral-signaling (MAVS) signaling, and we identify TNFα produced in response to MAVS signaling as pivotal in determining cell fate during SeV infection
We show that while cells harboring fulllength viral genomes die from virus-induced TNF-mediated apoptosis, cells enriched in DVGs regulate the expression and activity of a TNFR2/TNF receptor associated factor 1 (TRAF1) pro-survival program that protects them from TNF-induced apoptosis
Summary
Replication defective viral genomes (DVGs) generated during virus replication are the primary triggers of antiviral immunity in many RNA virus infections. Some species of DVGs can promote the establishment of persistent RSV, parainfluenza virus, measles virus, and other viruses during infections in tissue culture[11,12,13,14] and are proposed to be responsible for establishing persistent Ebola virus infections in humans[1] This pro-persistence activity of DVGs has been related to the continuous competition for the viral polymerase between full-length genomes and DVGs, resulting in alternating cycles of replication of full-length and defective genomes[15,16,17]. This mechanism cannot explain the survival of virus-infected cells in the presence of strong pro-apoptotic and antiviral molecules, including type I IFNs and TNFα, that are induced in response to sensing of DVGs10. This study reveals a mechanism by which distinct viral genomic products determine cell fate upon infection by taking advantage of the dual functions of TNFα to perpetuate both virus and host
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