Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes

Rimmelzwaan, Guus F.; Boon, Adrianus C. M.; Voeten, J.T.M.; Berkhoff, Eufemia; Fouchier, Ron A. M.; Osterhaus, Albert D. M. E.

doi:10.1016/j.virusres.2004.02.020

Cited by 94 publications

(73 citation statements)

References 13 publications

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“…The promiscuity of CD4 and CD8 T cell receptors could allow them to recognize epitopes even after the addition of a point mutation. While escape from CTLs is possible and observable [8][9][10][11], also observable are T cells that recognize a range of peptide sequences . In addition, the functional constraints placed on internal structural genes, inaccessible to antibodies, limit their ability to mutate.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

Laddy

Yan

Corbitt

et al. 2007

Vaccine

107

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The frequency of H5N1 avian influenza outbreaks in China and Eastern Europe has raised concern in the world health community regarding the potential for an influenza pandemic. Efforts to monitor the disease will only provide minimal warning in a global society, and steps must be taken to prevent the morbidity and mortality associated with past pandemics. The current stockpiling of antibody-inducing "bird flu" vaccines assumes the strain that emerges will be the same as strains currently circulating. We propose a novel consensus-based approach to vaccine development, employing a DNA vaccine strategy that can provide more highly cross-reactive cellular immunity against lethal influenza infection. We show such constructs can induce strong cellular immunity against H5 influenza antigens.

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Section: Introductionmentioning

confidence: 99%

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

Laddy

Yan

Corbitt

et al. 2007

Vaccine

107

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“…Also for influenza A viruses, a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from human CTL. One of them, the R-to-G substitution at position 384 (R384G), which is at the anchor residues of the HLA-B‫-1080ء‬restricted NP 380-388 and HLA-B‫-5072ء‬restricted NP 383-391 epitopes, resulted in the loss of these epitopes (51,58). This substitution reduced the in vitro virus-specific CTL response in HLA-B‫-5072ء‬positive individuals significantly (2).…”

mentioning

confidence: 99%

Functional Constraints of Influenza A Virus Epitopes Limit Escape from Cytotoxic T Lymphocytes

Berkhoff

Wit

Geelhoed-Mieras

et al. 2005

J Virol

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Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in CTL epitopes. Also for influenza A viruses a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from CTL. However, other previously identified influenza A virus CTL epitopes are highly conserved, including the immunodominant HLA-A‫-1020ء‬ restricted epitope from the matrix protein, M1 58-66 . We hypothesized that functional constraints were responsible for the conserved nature of influenza A virus CTL epitopes, limiting escape from CTL. To assess the impact of amino acid substitutions in conserved epitopes on viral fitness and recognition by specific CTL, we performed a mutational analysis of CTL epitopes. Both alanine replacements and more conservative substitutions were introduced at various positions of different influenza A virus CTL epitopes. Alanine replacements for each of the nine amino acids of the M1 58-66 epitope were tolerated to various extents, except for the anchor residue at the second position. Substitution of anchor residues in other influenza A virus CTL epitopes also affected viral fitness. Viable mutant viruses were used in CTL recognition experiments. The results are discussed in the light of the possibility of influenza viruses to escape from specific CTL. It was speculated that functional constraints limit variation in certain epitopes, especially at anchor residues, explaining the conserved nature of these epitopes. Cytotoxic T lymphocytes (CTL) play an important role in the control of viral infections (10).To evade these CTL responses, viruses can exploit a variety of mechanisms to prevent recognition by specific CTL, including the accumulation of amino acid substitutions in or adjacent to CTL epitopes (28, 39). This strategy has been shown predominantly by certain RNA viruses, such as human immunodeficiency virus (HIV) (7,21,22,35,44,47,48), hepatitis C virus (9, 60), and lymphocytic choriomeningitis virus (36, 46), which are known for their high mutation rate. Also for influenza A viruses, a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from human CTL. One of them, the R-to-G substitution at position 384 (R384G), which is at the anchor residues of the HLA-B‫-1080ء‬restricted NP 380-388 and HLA-B‫-5072ء‬restricted NP 383-391 epitopes, resulted in the loss of these epitopes (51,58). This substitution reduced the in vitro virus-specific CTL response in HLA-B‫-5072ء‬positive individuals significantly (2). Although the R384G substitution was tolerated only in the presence of one or more functionally compensating comutations (50, 52), it was fixed rapidly. This was explained by small selective advantages and population dynamics in a theoretical model (19). A third variable epitope in the influenza A virus NP is the HLA-B‫-1053ء‬restricted epitope NP [418][419][420][421][422][423][424][425][426] , which displayed considerable variability in T-cell contact ...

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“…This escape mechanism has been described predominantly for persistent virus infections. However, epitopes from the influenza virus nucleoprotein (NP) also exhibit amino acid variation associated with escape from recognition by CTLs (2,15,17). The rapid fixation of these mutations was explained by small selective advantages and population dynamics in a theoretical model, using the R384G mutation in the HLA-B*2705-restricted NP 383-391 epitope as an example (4).…”

mentioning

confidence: 99%

“…The rapid fixation of these mutations was explained by small selective advantages and population dynamics in a theoretical model, using the R384G mutation in the HLA-B*2705-restricted NP 383-391 epitope as an example (4). The R384G mutation resulted in the loss of the anchor residue and as a result ablated recognition by CTLs (15,17). The loss of this epitope affected the human in vitro CTL response significantly (1).…”

mentioning

confidence: 99%

Functional Compensation of a Detrimental Amino Acid Substitution in a Cytotoxic-T-Lymphocyte Epitope of Influenza A Viruses by Comutations

Rimmelzwaan

Berkhoff

Nieuwkoop

et al. 2004

J Virol

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Influenza A viruses accumulate amino acid substitutions in cytotoxic-T-lymphocyte (CTL) epitopes, allowing these viruses to escape from CTL immunity. The arginine-to-glycine substitution at position 384 of the viral nucleoprotein is associated with escape from CTLs. Introduction of the R384G substitution in the nucleoprotein gene segment of influenza virus A/Hong Kong/2/68 by site-directed mutagenesis was detrimental to viral fitness. Introduction of one of the comutations associated with R384G, E375G, partially restored viral fitness and nucleoprotein functionality. We hypothesized that influenza A viruses need to overcome functional constraints to accumulate mutations in CTL epitopes and escape from CTLs

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Sequence variation in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes

Cited by 94 publications

References 13 publications

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

Immunogenicity of novel consensus-based DNA vaccines against avian influenza

Functional Constraints of Influenza A Virus Epitopes Limit Escape from Cytotoxic T Lymphocytes

Functional Compensation of a Detrimental Amino Acid Substitution in a Cytotoxic-T-Lymphocyte Epitope of Influenza A Viruses by Comutations

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