Abstract
Intra-host sequence data from RNA viruses have revealed the ubiquity of defective viruses in natural viral populations, sometimes at surprisingly high frequency. Although defective viruses have long been known to laboratory virologists, their relevance in clinical and epidemiological settings has not been established. The discovery of long-term transmission of a defective lineage of dengue virus type 1 (DENV-1) in Myanmar, first seen in 2001, raised important questions about the emergence of transmissible defective viruses and their role in viral epidemiology. By combining phylogenetic analyses and dynamical modeling, we investigate how evolutionary and ecological processes at the intra-host and inter-host scales shaped the emergence and spread of the defective DENV-1 lineage. We show that this lineage of defective viruses emerged between June 1998 and February 2001, and that the defective virus was transmitted primarily through co-transmission with the functional virus to uninfected individuals. We provide evidence that, surprisingly, this co-transmission route has a higher transmission potential than transmission of functional dengue viruses alone. Consequently, we predict that the defective lineage should increase overall incidence of dengue infection, which could account for the historically high dengue incidence reported in Myanmar in 2001–2002. Our results show the unappreciated potential for defective viruses to impact the epidemiology of human pathogens, possibly by modifying the virulence-transmissibility trade-off, or to emerge as circulating infections in their own right. They also demonstrate that interactions between viral variants, such as complementation, can open new pathways to viral emergence.
Highlights
The high deleterious mutation rate of RNA viruses ensures that many genomes are defective [1], the long-term evolutionary and epidemiological consequences of the presence and transmission of defective viruses rarely have been discussed
We show that the defective lineage emerged from circulating dengue viruses between June 1998 and February 2001, and that it spreads because—surprisingly—its presence causes functional dengue viruses to transmit more efficiently
Our model shows that this would cause a substantial rise in total dengue infections, consistent with historically high levels of dengue cases reported in Myanmar during 2001 and 2002
Summary
The high deleterious mutation rate of RNA viruses ensures that many genomes are defective [1], the long-term evolutionary and epidemiological consequences of the presence and transmission of defective viruses rarely have been discussed. Defective viruses with full-length genomes have been recognized as a general phenomenon in many major human pathogens, including human immunodeficiency virus, hepatitis B virus, hepatitis C virus, West Nile virus, and dengue virus [2,9,10,11,12,13,14,15,16]. The role they play in natural viral populations is unclear [17] and an epidemiological impact has not been demonstrated
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