Why do defective viral genomes contribute to persistent infection?
Some viruses often cause acute infections, such as RSV, measles, and Ebola. But sometimes, these viruses trigger persistent infections following acute infections. Why this occurs remains largely unknown.
Now a novel study appearing in Nature Communications provides an explanation for it. Led by researchers from the University of Pennsylvania, the study reveals a mechanism by which defective viral genomes (DVGs) generated during virus replication help infected cells survive.
DVGs are truncated forms of the viral genome that are generated during virus replication when the virus reaches high titers. It is well-established that the accumulation of DVGs in infected cells is the primary trigger of antiviral immunity. Paradoxically, DVGs have been found to promote viral persistence.
Dr. Carolina López at the University of Pennsylvania has been studying the functions of DVGs for a long period of time. The laboratory of Dr. López focuses on discovering signals that regulate the immune system during viral infections and developing vaccines and antiviral therapies.
Dr. López and colleagues designed a technique to distinguish DVGs from full-length viral genomes in individual cells. The technique involves the use of two different types of labeled probes. With the help of the technique, they analyzed cell lines infected with SeV or RSV. The analysis revealed the differential accumulation of DVGs and full-length viral genomes among infected cells. Only a subpopulation of infected cells had high levels of DVGs. Other infected cells had almost no DVGs.
Further, DVG-enriched cells were less prone to apoptosis during infection and survived longer than cells enriched in full-length viral genomes, suggesting that DVGs promote the survival of infected cells and contribute to persistent infections. To uncover the underlying mechanism, the researchers examined gene expression in DVG-enriched cells and cells harboring full-length viral genomes. It showed that several genes that promote cell survival were upregulated in DVG-enriched cells, including TNFR2 and TRAF1
, so that these cells were protected from TNFα-mediated apoptosis. In contrast, the cells harboring full-length viral genomes were susceptible to TNFα-induced apoptosis.
In conclusion, the discoveries provide a mechanism that DVGs promote persistent viral infections and fundamentally change our understanding of virus-host interactions.