Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain

Sarah Louise Fordyce; Karoline Bragstad; Svend Stenvang Pedersen; Thøger G. Jensen; Bente Gahrn-Hansen; Rod Daniels; Alan Hay; Marie-Louise Kampmann; Christian Anders Wathne Bruhn; José Victor Moreno Mayar; Maria del Carmen Avila Arcos; Tom Gilbert; Lars P. Nielsen

doi:10.1186/1743-422X-10-116

Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain

Sarah Louise Fordyce, Karoline Bragstad, Svend Stenvang Pedersen, Thøger G. Jensen, Bente Gahrn-Hansen, Rod Daniels, Alan Hay, Marie-Louise Kampmann, Christian Anders Wathne Bruhn, José Victor Moreno Mayar, Maria del Carmen Avila Arcos, Tom Gilbert, Lars P. Nielsen

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Abstract

Background: Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. Methods. Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. Results: No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. Conclusions: Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck.

Original language	English
Article number	116
Journal	Virology Journal
Volume	10
Number of pages	9
ISSN	1743-422X
DOIs	https://doi.org/10.1186/1743-422X-10-116
Publication status	Published - 2013

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Fordyce, S. L., Bragstad, K., Pedersen, S. S., Jensen, T. G., Gahrn-Hansen, B., Daniels, R., Hay, A., Kampmann, M-L., Bruhn, C. A. W., Moreno Mayar, J. V., Avila Arcos, M. D. C., Gilbert, T., & Nielsen, L. P. (2013). Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain. Virology Journal, 10, [116]. https://doi.org/10.1186/1743-422X-10-116

@article{2aa3764bbbc548a79b24253814ddb7be,

title = "Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain",

abstract = "Background: Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. Methods. Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. Results: No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. Conclusions: Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck.",

author = "Fordyce, {Sarah Louise} and Karoline Bragstad and Pedersen, {Svend Stenvang} and Jensen, {Th{\o}ger G.} and Bente Gahrn-Hansen and Rod Daniels and Alan Hay and Marie-Louise Kampmann and Bruhn, {Christian Anders Wathne} and {Moreno Mayar}, {Jos{\'e} Victor} and {Avila Arcos}, {Maria del Carmen} and Tom Gilbert and Nielsen, {Lars P.}",

year = "2013",

doi = "10.1186/1743-422X-10-116",

language = "English",

volume = "10",

journal = "Virology Journal",

issn = "1743-422X",

publisher = "BioMed Central",

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TY - JOUR

T1 - Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain

AU - Fordyce, Sarah Louise

AU - Bragstad, Karoline

AU - Pedersen, Svend Stenvang

AU - Jensen, Thøger G.

AU - Gahrn-Hansen, Bente

AU - Daniels, Rod

AU - Hay, Alan

AU - Kampmann, Marie-Louise

AU - Bruhn, Christian Anders Wathne

AU - Moreno Mayar, José Victor

AU - Avila Arcos, Maria del Carmen

AU - Gilbert, Tom

AU - Nielsen, Lars P.

PY - 2013

Y1 - 2013

N2 - Background: Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. Methods. Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. Results: No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. Conclusions: Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck.

AB - Background: Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. Methods. Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. Results: No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. Conclusions: Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck.

U2 - 10.1186/1743-422X-10-116

DO - 10.1186/1743-422X-10-116

M3 - Journal article

C2 - 23587185

SN - 1743-422X

VL - 10

JO - Virology Journal

JF - Virology Journal

M1 - 116

ER -

Genetic diversity among pandemic 2009 influenza viruses isolated from a transmission chain

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