Limits...
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.

Show MeSH

Related in: MedlinePlus

Schematic diagrams for different transmission routes of tDP and the compartmental model for tDP and DENV-1 transmission.(A and B) Two possible routes of tDP transmission. The tDP can replicate only in dually infected individuals, so these individuals are the only source for transmission of tDP. We consider situations where a dually infected ‘donor host’ contacts a ‘recipient host’ that is either uninfected and completely susceptible (in panel A) or infected with the functional virus (DENV-1) only (in panel B). By chance, the viral population that is transmitted to the recipient host may contain the tDPs only (P), the functional virus only (Q), or both types of particles (W). If the transmitted viral population consists of only the functional virus, the recipient host would become a DENV-1-only infected individual. If this viral population consists of both types of particles, it is possible for the recipient host to become a dually infected individual, irrespective of whether the recipient host is already infected or not. However, if the transmitted viral population consists of only tDP particles, the recipient host can become dually infected only if it is already infected with DENV-1 as shown in panel B (a pathway we call super-infection). (C) Schematic for the compartmental model of DENV-1 and tDP transmission dynamics. S, E, I and R denote the susceptible, exposed, infectious, recovered compartments for the functional virus, respectively. G and D are the exposed and infectious compartments for dual infection, respectively. σ and γ denote the rates at which latent individuals become infectious and infectious individuals recover, respectively. Dashed lines denote processes with rates that are orders of magnitude lower than rates shown with solid lines. The mathematical expressions show the infectious population groups that contribute to each route of transmission, and associated scaling parameters. Model equations are shown in Eqn. (1) of the Methods.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585136&req=5

ppat-1003193-g002: Schematic diagrams for different transmission routes of tDP and the compartmental model for tDP and DENV-1 transmission.(A and B) Two possible routes of tDP transmission. The tDP can replicate only in dually infected individuals, so these individuals are the only source for transmission of tDP. We consider situations where a dually infected ‘donor host’ contacts a ‘recipient host’ that is either uninfected and completely susceptible (in panel A) or infected with the functional virus (DENV-1) only (in panel B). By chance, the viral population that is transmitted to the recipient host may contain the tDPs only (P), the functional virus only (Q), or both types of particles (W). If the transmitted viral population consists of only the functional virus, the recipient host would become a DENV-1-only infected individual. If this viral population consists of both types of particles, it is possible for the recipient host to become a dually infected individual, irrespective of whether the recipient host is already infected or not. However, if the transmitted viral population consists of only tDP particles, the recipient host can become dually infected only if it is already infected with DENV-1 as shown in panel B (a pathway we call super-infection). (C) Schematic for the compartmental model of DENV-1 and tDP transmission dynamics. S, E, I and R denote the susceptible, exposed, infectious, recovered compartments for the functional virus, respectively. G and D are the exposed and infectious compartments for dual infection, respectively. σ and γ denote the rates at which latent individuals become infectious and infectious individuals recover, respectively. Dashed lines denote processes with rates that are orders of magnitude lower than rates shown with solid lines. The mathematical expressions show the infectious population groups that contribute to each route of transmission, and associated scaling parameters. Model equations are shown in Eqn. (1) of the Methods.

Mentions: To identify potential mechanisms that allow for sustained transmission of the tDP, we constructed a seasonally forced dynamical model for the transmission dynamics of the tDP and DENV-1 by combining aspects of established models for dengue [34] and defective particles [7] (see Methods and Text S1). We first focus on the possible mechanisms of transmission of tDPs. The donor host (either human or mosquito) must be dually infected with DENV-1 and tDP, and we consider two types of contacts that may lead to tDP transmission (Fig. 2A and B): contact either with uninfected susceptible individuals (possibly leading to infection of the susceptible with one or both viruses) or with individuals infected with DENV-1 only (possibly leading to super-infection with tDP). Three types of transmission events are possible: transmission of tDP only (which matters only if the host is already infected with DENV-1), transmission of DENV-1 only, or transmission of both tDP and DENV-1. The rates at which these three alternatives occur, relative to the rate of transmission of the functional virus from DENV-1-infected hosts, are modeled using dimensionless scaling parameters P, Q and W, respectively (Fig. 2C). These three parameters incorporate the changes in viral transmission rates from dually infected human and mosquito individuals as a result of all relevant factors including changes in viral titers and host movement or behavior patterns.


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)

Schematic diagrams for different transmission routes of tDP and the compartmental model for tDP and DENV-1 transmission.(A and B) Two possible routes of tDP transmission. The tDP can replicate only in dually infected individuals, so these individuals are the only source for transmission of tDP. We consider situations where a dually infected ‘donor host’ contacts a ‘recipient host’ that is either uninfected and completely susceptible (in panel A) or infected with the functional virus (DENV-1) only (in panel B). By chance, the viral population that is transmitted to the recipient host may contain the tDPs only (P), the functional virus only (Q), or both types of particles (W). If the transmitted viral population consists of only the functional virus, the recipient host would become a DENV-1-only infected individual. If this viral population consists of both types of particles, it is possible for the recipient host to become a dually infected individual, irrespective of whether the recipient host is already infected or not. However, if the transmitted viral population consists of only tDP particles, the recipient host can become dually infected only if it is already infected with DENV-1 as shown in panel B (a pathway we call super-infection). (C) Schematic for the compartmental model of DENV-1 and tDP transmission dynamics. S, E, I and R denote the susceptible, exposed, infectious, recovered compartments for the functional virus, respectively. G and D are the exposed and infectious compartments for dual infection, respectively. σ and γ denote the rates at which latent individuals become infectious and infectious individuals recover, respectively. Dashed lines denote processes with rates that are orders of magnitude lower than rates shown with solid lines. The mathematical expressions show the infectious population groups that contribute to each route of transmission, and associated scaling parameters. Model equations are shown in Eqn. (1) of the Methods.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585136&req=5

ppat-1003193-g002: Schematic diagrams for different transmission routes of tDP and the compartmental model for tDP and DENV-1 transmission.(A and B) Two possible routes of tDP transmission. The tDP can replicate only in dually infected individuals, so these individuals are the only source for transmission of tDP. We consider situations where a dually infected ‘donor host’ contacts a ‘recipient host’ that is either uninfected and completely susceptible (in panel A) or infected with the functional virus (DENV-1) only (in panel B). By chance, the viral population that is transmitted to the recipient host may contain the tDPs only (P), the functional virus only (Q), or both types of particles (W). If the transmitted viral population consists of only the functional virus, the recipient host would become a DENV-1-only infected individual. If this viral population consists of both types of particles, it is possible for the recipient host to become a dually infected individual, irrespective of whether the recipient host is already infected or not. However, if the transmitted viral population consists of only tDP particles, the recipient host can become dually infected only if it is already infected with DENV-1 as shown in panel B (a pathway we call super-infection). (C) Schematic for the compartmental model of DENV-1 and tDP transmission dynamics. S, E, I and R denote the susceptible, exposed, infectious, recovered compartments for the functional virus, respectively. G and D are the exposed and infectious compartments for dual infection, respectively. σ and γ denote the rates at which latent individuals become infectious and infectious individuals recover, respectively. Dashed lines denote processes with rates that are orders of magnitude lower than rates shown with solid lines. The mathematical expressions show the infectious population groups that contribute to each route of transmission, and associated scaling parameters. Model equations are shown in Eqn. (1) of the Methods.
Mentions: To identify potential mechanisms that allow for sustained transmission of the tDP, we constructed a seasonally forced dynamical model for the transmission dynamics of the tDP and DENV-1 by combining aspects of established models for dengue [34] and defective particles [7] (see Methods and Text S1). We first focus on the possible mechanisms of transmission of tDPs. The donor host (either human or mosquito) must be dually infected with DENV-1 and tDP, and we consider two types of contacts that may lead to tDP transmission (Fig. 2A and B): contact either with uninfected susceptible individuals (possibly leading to infection of the susceptible with one or both viruses) or with individuals infected with DENV-1 only (possibly leading to super-infection with tDP). Three types of transmission events are possible: transmission of tDP only (which matters only if the host is already infected with DENV-1), transmission of DENV-1 only, or transmission of both tDP and DENV-1. The rates at which these three alternatives occur, relative to the rate of transmission of the functional virus from DENV-1-infected hosts, are modeled using dimensionless scaling parameters P, Q and W, respectively (Fig. 2C). These three parameters incorporate the changes in viral transmission rates from dually infected human and mosquito individuals as a result of all relevant factors including changes in viral titers and host movement or behavior patterns.

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