Redundancy of the influenza A virus-specific cytotoxic T lymphocyte response in HLA-B*2705 transgenic mice limits the impact of a mutation in the immunodominant NP383-391 epitope on influenza pathogenesis

R. Bodewes, M. M. Geelhoed-Mieras, N. J. Nieuwkoop, J. A. Hanson, C. S. David, R. A M Fouchier, A. D M E Osterhaus, G. F. Rimmelzwaan

Research output: Contribution to journalArticle

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Abstract

During the 1993-1994 flu season, influenza A/H3N2 viruses emerged with an amino acid substitution (R384G) at the anchor residue of the HLA-B*2705 restricted NP383-391 epitope located in the nucleoprotein (NP). The R384G substitution reached fixation rapidly and abrogated recognition of A/H3N2 viruses by NP383-391-specific CD8+ T cytotoxic T lymphocytes (CTL) completely. To test the impact of the R384G substitution in the immunodominant NP383-391 epitope in vivo, influenza A viruses that differ at position 384 of the NP only were generated by reverse genetics. These viruses with an arginin (384R) or a glycin (384G) at position 384 were used to inoculate HLA-B*2705-transgenic mice and C57Bl/6 mice. Infection of naïve C57Bl/6 and HLA-B*2705 mice with influenza virus containing the NP383-391 epitope (384R) caused more weight loss compared to infection with the virus without the epitope (384G). In contrast, HLA-B*2705 transgenic mice primed for a secondary CTL response by infection with a heterosubtypic influenza A virus, did not display this difference in virulence and the outcome of infection with the 384R virus was somewhat reduced. This phenotype of the 384R-virus was not observed in primed C57Bl/6 mice lacking HLA-B*2705. The relative reduction of weight loss after infection of primed HLA-B*2705+ mice with the 384R virus correlated with the CTL response to the NP383-391. However, no differences were observed in the kinetics of viral clearance between the two viruses in immune HLA-B*2705+ mice, which may be attributed at least partially to CTL responses to other HLA-B*2705 restricted epitopes that were similar in magnitude.

Original languageEnglish (US)
Pages (from-to)123-130
Number of pages8
JournalVirus Research
Volume155
Issue number1
DOIs
StatePublished - Jan 2011

Fingerprint

Influenza A virus
Cytotoxic T-Lymphocytes
Human Influenza
Transgenic Mice
Epitopes
Mutation
Viruses
H3N2 Subtype Influenza A Virus
Nucleoproteins
Infection
Weight Loss
Reverse Genetics
HLA-B*27:05 antigen
Virus Diseases
Amino Acid Substitution
Orthomyxoviridae
Virulence
Phenotype

Keywords

  • 2705 Transgenic mice
  • Cytotoxic T lymphocytes
  • HLA-B
  • Influenza

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases
  • Cancer Research

Cite this

Redundancy of the influenza A virus-specific cytotoxic T lymphocyte response in HLA-B*2705 transgenic mice limits the impact of a mutation in the immunodominant NP383-391 epitope on influenza pathogenesis. / Bodewes, R.; Geelhoed-Mieras, M. M.; Nieuwkoop, N. J.; Hanson, J. A.; David, C. S.; Fouchier, R. A M; Osterhaus, A. D M E; Rimmelzwaan, G. F.

In: Virus Research, Vol. 155, No. 1, 01.2011, p. 123-130.

Research output: Contribution to journalArticle

Bodewes, R. ; Geelhoed-Mieras, M. M. ; Nieuwkoop, N. J. ; Hanson, J. A. ; David, C. S. ; Fouchier, R. A M ; Osterhaus, A. D M E ; Rimmelzwaan, G. F. / Redundancy of the influenza A virus-specific cytotoxic T lymphocyte response in HLA-B*2705 transgenic mice limits the impact of a mutation in the immunodominant NP383-391 epitope on influenza pathogenesis. In: Virus Research. 2011 ; Vol. 155, No. 1. pp. 123-130.
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abstract = "During the 1993-1994 flu season, influenza A/H3N2 viruses emerged with an amino acid substitution (R384G) at the anchor residue of the HLA-B*2705 restricted NP383-391 epitope located in the nucleoprotein (NP). The R384G substitution reached fixation rapidly and abrogated recognition of A/H3N2 viruses by NP383-391-specific CD8+ T cytotoxic T lymphocytes (CTL) completely. To test the impact of the R384G substitution in the immunodominant NP383-391 epitope in vivo, influenza A viruses that differ at position 384 of the NP only were generated by reverse genetics. These viruses with an arginin (384R) or a glycin (384G) at position 384 were used to inoculate HLA-B*2705-transgenic mice and C57Bl/6 mice. Infection of na{\"i}ve C57Bl/6 and HLA-B*2705 mice with influenza virus containing the NP383-391 epitope (384R) caused more weight loss compared to infection with the virus without the epitope (384G). In contrast, HLA-B*2705 transgenic mice primed for a secondary CTL response by infection with a heterosubtypic influenza A virus, did not display this difference in virulence and the outcome of infection with the 384R virus was somewhat reduced. This phenotype of the 384R-virus was not observed in primed C57Bl/6 mice lacking HLA-B*2705. The relative reduction of weight loss after infection of primed HLA-B*2705+ mice with the 384R virus correlated with the CTL response to the NP383-391. However, no differences were observed in the kinetics of viral clearance between the two viruses in immune HLA-B*2705+ mice, which may be attributed at least partially to CTL responses to other HLA-B*2705 restricted epitopes that were similar in magnitude.",
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AU - Hanson, J. A.

AU - David, C. S.

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