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Phylodynamic analysis of the emergence and epidemiological impact of transmissible defective dengue viruses.

Ke R, Aaskov J, Holmes EC, Lloyd-Smith JO - PLoS Pathog. (2013)

Bottom Line: 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.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.They also demonstrate that interactions between viral variants, such as complementation, can open new pathways to viral emergence.

View Article: PubMed Central - PubMed

Affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California, United States of America. ruian@ucla.edu

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.

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Increasing Reff,co above 1 leads to increases in the fraction of dually infected individuals among all infected individuals and in the total number of infected individuals.The y-axis shows the predicted fold increase in total DENV-1 infected humans during 2001 and 2002 relative to the number of human cases in the absence of tDP. The x-axis shows the predicted fraction of human cases who were dually infected during 2002. The color of the dots indicates the value of Reff,co as shown in the color bar. Only simulations with Reff,co>1 are shown; when Reff,co<1, the fraction of dually infected humans is near 0 and the fold increase in total dengue cases is near 1. 10,000 sets of parameter values were sampled using Latin hypercube sampling. P and Q were sampled from a uniform distribution between 0 and 1 and W was sampled from a uniform distribution between 0 and 2. γH,D and σV,D were sampled in a way such that the fold changes in human infectious period (γH,D/γH) and mosquito incubation period (σV,D/σV) range from 0.5 to 2. The values of γH, σV and μV are kept constant.
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ppat-1003193-g004: Increasing Reff,co above 1 leads to increases in the fraction of dually infected individuals among all infected individuals and in the total number of infected individuals.The y-axis shows the predicted fold increase in total DENV-1 infected humans during 2001 and 2002 relative to the number of human cases in the absence of tDP. The x-axis shows the predicted fraction of human cases who were dually infected during 2002. The color of the dots indicates the value of Reff,co as shown in the color bar. Only simulations with Reff,co>1 are shown; when Reff,co<1, the fraction of dually infected humans is near 0 and the fold increase in total dengue cases is near 1. 10,000 sets of parameter values were sampled using Latin hypercube sampling. P and Q were sampled from a uniform distribution between 0 and 1 and W was sampled from a uniform distribution between 0 and 2. γH,D and σV,D were sampled in a way such that the fold changes in human infectious period (γH,D/γH) and mosquito incubation period (σV,D/σV) range from 0.5 to 2. The values of γH, σV and μV are kept constant.

Mentions: To assess the possible epidemiological impact of tDP emergence, we simulated the full model from the emergence of tDP (assumed here to occur in year 2000) through the period for which we have data (to the end of 2002), for a range of biologically plausible parameter values (see Methods). We randomly sampled the four parameters that determine the value of Reff,co, and the two additional transmission parameters P and Q, and computed the value of Reff,co for each simulation. When Reff,co<1, the fraction of human cases that were dually infected in year 2002 was negligible, and the total number of dengue cases during the three years after tDP emergence did not change appreciably from the number in the absence of tDP. In contrast, values of Reff,co>1 led to increases in both the fraction of dengue-infected humans who were dually infected and in the total number of dengue cases (Fig. 4). Interestingly, the model reveals a lower bound of the fold increase in total dengue cases for a given observed fraction of dually infected individuals. This is because increases in the fraction of dually infected individuals result from more efficient co-transmission, which also increases the total number of infected individuals. Aaskov et al. reported that 5 out of 5 human patients sampled in 2002 were dually infected [14]. With reference to the results in Fig. 4, the observation that all cases were dually infected in 2002 predicts a 2.5–4 fold increase in total dengue cases during 2001 and 2002, though of course the sample size is small so uncertainties are large. (For 5/5, the lower bound of the 95% C.I. for the proportion is 0.48, which corresponds to a lower bound of a 1.3 fold increase in total cases.)


Phylodynamic analysis of the emergence and epidemiological impact of transmissible defective dengue viruses.

Ke R, Aaskov J, Holmes EC, Lloyd-Smith JO - PLoS Pathog. (2013)

Increasing Reff,co above 1 leads to increases in the fraction of dually infected individuals among all infected individuals and in the total number of infected individuals.The y-axis shows the predicted fold increase in total DENV-1 infected humans during 2001 and 2002 relative to the number of human cases in the absence of tDP. The x-axis shows the predicted fraction of human cases who were dually infected during 2002. The color of the dots indicates the value of Reff,co as shown in the color bar. Only simulations with Reff,co>1 are shown; when Reff,co<1, the fraction of dually infected humans is near 0 and the fold increase in total dengue cases is near 1. 10,000 sets of parameter values were sampled using Latin hypercube sampling. P and Q were sampled from a uniform distribution between 0 and 1 and W was sampled from a uniform distribution between 0 and 2. γH,D and σV,D were sampled in a way such that the fold changes in human infectious period (γH,D/γH) and mosquito incubation period (σV,D/σV) range from 0.5 to 2. The values of γH, σV and μV are kept constant.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585136&req=5

ppat-1003193-g004: Increasing Reff,co above 1 leads to increases in the fraction of dually infected individuals among all infected individuals and in the total number of infected individuals.The y-axis shows the predicted fold increase in total DENV-1 infected humans during 2001 and 2002 relative to the number of human cases in the absence of tDP. The x-axis shows the predicted fraction of human cases who were dually infected during 2002. The color of the dots indicates the value of Reff,co as shown in the color bar. Only simulations with Reff,co>1 are shown; when Reff,co<1, the fraction of dually infected humans is near 0 and the fold increase in total dengue cases is near 1. 10,000 sets of parameter values were sampled using Latin hypercube sampling. P and Q were sampled from a uniform distribution between 0 and 1 and W was sampled from a uniform distribution between 0 and 2. γH,D and σV,D were sampled in a way such that the fold changes in human infectious period (γH,D/γH) and mosquito incubation period (σV,D/σV) range from 0.5 to 2. The values of γH, σV and μV are kept constant.
Mentions: To assess the possible epidemiological impact of tDP emergence, we simulated the full model from the emergence of tDP (assumed here to occur in year 2000) through the period for which we have data (to the end of 2002), for a range of biologically plausible parameter values (see Methods). We randomly sampled the four parameters that determine the value of Reff,co, and the two additional transmission parameters P and Q, and computed the value of Reff,co for each simulation. When Reff,co<1, the fraction of human cases that were dually infected in year 2002 was negligible, and the total number of dengue cases during the three years after tDP emergence did not change appreciably from the number in the absence of tDP. In contrast, values of Reff,co>1 led to increases in both the fraction of dengue-infected humans who were dually infected and in the total number of dengue cases (Fig. 4). Interestingly, the model reveals a lower bound of the fold increase in total dengue cases for a given observed fraction of dually infected individuals. This is because increases in the fraction of dually infected individuals result from more efficient co-transmission, which also increases the total number of infected individuals. Aaskov et al. reported that 5 out of 5 human patients sampled in 2002 were dually infected [14]. With reference to the results in Fig. 4, the observation that all cases were dually infected in 2002 predicts a 2.5–4 fold increase in total dengue cases during 2001 and 2002, though of course the sample size is small so uncertainties are large. (For 5/5, the lower bound of the 95% C.I. for the proportion is 0.48, which corresponds to a lower bound of a 1.3 fold increase in total cases.)

Bottom Line: 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.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.They also demonstrate that interactions between viral variants, such as complementation, can open new pathways to viral emergence.

View Article: PubMed Central - PubMed

Affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California, United States of America. ruian@ucla.edu

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.

Show MeSH
Related in: MedlinePlus