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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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The tDP is primarily transmitted through the co-infection of susceptible individuals.(A) The ratio of the cumulative number of dually infected humans (D) over the cumulative number of humans infected with DENV-1 only (I) during the 2nd and 3rd years after tDP emergence (corresponding to calendar year 2001 and 2002) is plotted against the parameter W describing the efficiency of co-transmission. (B) The fraction of super-infected humans among all dually infected humans for different values of the co-transmission coefficient. Simulation results where tDP is and is not transmitted persistently during the 3rd year of the simulation are denoted as red and gray dots, respectively. Vertical dashed lines denote the threshold of W = 1, whereas the horizontal dashed line in panel A denotes the threshold where the number of dually infected cases is equal to the number of singly infected cases. 1,000 samples of Latin hypercube sampling were performed with parameters P and Q sampled uniformly between 0 and 1 and W sampled uniformly between 0 and 1.3.
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ppat-1003193-g003: The tDP is primarily transmitted through the co-infection of susceptible individuals.(A) The ratio of the cumulative number of dually infected humans (D) over the cumulative number of humans infected with DENV-1 only (I) during the 2nd and 3rd years after tDP emergence (corresponding to calendar year 2001 and 2002) is plotted against the parameter W describing the efficiency of co-transmission. (B) The fraction of super-infected humans among all dually infected humans for different values of the co-transmission coefficient. Simulation results where tDP is and is not transmitted persistently during the 3rd year of the simulation are denoted as red and gray dots, respectively. Vertical dashed lines denote the threshold of W = 1, whereas the horizontal dashed line in panel A denotes the threshold where the number of dually infected cases is equal to the number of singly infected cases. 1,000 samples of Latin hypercube sampling were performed with parameters P and Q sampled uniformly between 0 and 1 and W sampled uniformly between 0 and 1.3.

Mentions: To investigate the key mechanisms contributing to tDP emergence and transmission, we simulated the model with different values of P, Q and W while holding other parameters constant. Note that the values of P and Q, i.e. transmission of tDP only and DENV-1 only, are probably small because of the high number of viruses thought to be transmitted between human and mosquito [35]. Nonetheless, we allow them to vary in a wide range (0 to 1) to be comprehensive. We found that the essential determinant of long-term transmission of the tDP is the value of parameter W, i.e. the efficiency of co-transmission of both the tDP and functional DENV-1. Continuous transmission of the tDP over multiple years requires that co-transmission of tDP and DENV-1 is more efficient than transmission of wild-type DENV-1 in the absence of tDP (i.e. W>1.0, irrespective of the values of P and Q, as shown in Fig. 3A). For the abundance of dually infected individuals (D) to rise to a level comparable to DENV-1 infected individuals (I) within 3 years, as observed in the data from Myanmar, the co-transmission of tDP and DENV-1 must be 15% more efficient than the wild-type transmission (W>1.15, red dots above the horizontal dashed line in Fig. 3A), averaging over humans and mosquitoes. An alternative explanation of the observed rise in frequency of dually infected individuals is genetic drift without any transmission advantage. To test the validity of our deterministic modeling approach, we conducted a stochastic analysis based on a Wright-Fisher model and found that the probability that the observed rise in frequency occurred due to purely neutral evolution is extremely small (see Text S1 for details). Therefore, from epidemiological arguments, transmission of tDP is driven primarily by co-transmission of tDP and DENV-1, which is more efficient than transmission of DENV-1 by singly-infected hosts. However, in simulations with considerably higher values of W, both DENV-1 and the tDP go extinct due to depletion of susceptible individuals during the post-epidemic refractory period.


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)

The tDP is primarily transmitted through the co-infection of susceptible individuals.(A) The ratio of the cumulative number of dually infected humans (D) over the cumulative number of humans infected with DENV-1 only (I) during the 2nd and 3rd years after tDP emergence (corresponding to calendar year 2001 and 2002) is plotted against the parameter W describing the efficiency of co-transmission. (B) The fraction of super-infected humans among all dually infected humans for different values of the co-transmission coefficient. Simulation results where tDP is and is not transmitted persistently during the 3rd year of the simulation are denoted as red and gray dots, respectively. Vertical dashed lines denote the threshold of W = 1, whereas the horizontal dashed line in panel A denotes the threshold where the number of dually infected cases is equal to the number of singly infected cases. 1,000 samples of Latin hypercube sampling were performed with parameters P and Q sampled uniformly between 0 and 1 and W sampled uniformly between 0 and 1.3.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585136&req=5

ppat-1003193-g003: The tDP is primarily transmitted through the co-infection of susceptible individuals.(A) The ratio of the cumulative number of dually infected humans (D) over the cumulative number of humans infected with DENV-1 only (I) during the 2nd and 3rd years after tDP emergence (corresponding to calendar year 2001 and 2002) is plotted against the parameter W describing the efficiency of co-transmission. (B) The fraction of super-infected humans among all dually infected humans for different values of the co-transmission coefficient. Simulation results where tDP is and is not transmitted persistently during the 3rd year of the simulation are denoted as red and gray dots, respectively. Vertical dashed lines denote the threshold of W = 1, whereas the horizontal dashed line in panel A denotes the threshold where the number of dually infected cases is equal to the number of singly infected cases. 1,000 samples of Latin hypercube sampling were performed with parameters P and Q sampled uniformly between 0 and 1 and W sampled uniformly between 0 and 1.3.
Mentions: To investigate the key mechanisms contributing to tDP emergence and transmission, we simulated the model with different values of P, Q and W while holding other parameters constant. Note that the values of P and Q, i.e. transmission of tDP only and DENV-1 only, are probably small because of the high number of viruses thought to be transmitted between human and mosquito [35]. Nonetheless, we allow them to vary in a wide range (0 to 1) to be comprehensive. We found that the essential determinant of long-term transmission of the tDP is the value of parameter W, i.e. the efficiency of co-transmission of both the tDP and functional DENV-1. Continuous transmission of the tDP over multiple years requires that co-transmission of tDP and DENV-1 is more efficient than transmission of wild-type DENV-1 in the absence of tDP (i.e. W>1.0, irrespective of the values of P and Q, as shown in Fig. 3A). For the abundance of dually infected individuals (D) to rise to a level comparable to DENV-1 infected individuals (I) within 3 years, as observed in the data from Myanmar, the co-transmission of tDP and DENV-1 must be 15% more efficient than the wild-type transmission (W>1.15, red dots above the horizontal dashed line in Fig. 3A), averaging over humans and mosquitoes. An alternative explanation of the observed rise in frequency of dually infected individuals is genetic drift without any transmission advantage. To test the validity of our deterministic modeling approach, we conducted a stochastic analysis based on a Wright-Fisher model and found that the probability that the observed rise in frequency occurred due to purely neutral evolution is extremely small (see Text S1 for details). Therefore, from epidemiological arguments, transmission of tDP is driven primarily by co-transmission of tDP and DENV-1, which is more efficient than transmission of DENV-1 by singly-infected hosts. However, in simulations with considerably higher values of W, both DENV-1 and the tDP go extinct due to depletion of susceptible individuals during the post-epidemic refractory period.

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