As a result, DVGs cannot complete a full replication cycle. These DVGs manifest as genomes with complementary ends, deleterious point mutations, deletions, insertions, mosaic rearrangements, or a combination of these. Viral infections give rise to degenerate forms of the viral genome, known as defective viral genomes (DVGs), as a by-product of virus replication. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. Thus, innovative strategies for their control and prevention are urgently needed. Nature Communications volume 12, Article number: 2290 ( 2021)Īrthropod-borne viruses pose a major threat to global public health. Defective viral genomes as therapeutic interfering particles against flavivirus infection in mammalian and mosquito hosts
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