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

Rimmelzwaan, Guus F.; Berkhoff, Eufemia; Nieuwkoop, Nella J.; Fouchier, Ron A. M.; Osterhaus, Albert D. M. E.

doi:10.1128/jvi.78.16.8946-8949.2004

Cited by 43 publications

(46 citation statements)

References 18 publications

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“…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).…”

mentioning

confidence: 97%

“…2A and B). In addition, conservative amino acid substitutions at the anchor residues of the HLA-A‫-1010ء‬restricted epitopes PB1 591-599 (VSDGGPNLY) and NP [44][45][46][47][48][49][50][51][52] (CTELKLSDY) and the HLA-B‫-5072ء‬restricted epitope NP 174-184 (RRSGAAGA AVK) were introduced. The D593N substitution in PB1 was detrimental to viral fitness.…”

Section: Vol 79 2005 Influenza a Virus Epitopes And Escape From Ctlmentioning

confidence: 99%

“…Generation of CD8 ϩ -T-cell clones directed against the HLA-A‫-1020ء‬restricted epitope M1 [58][59][60][61][62][63][64][65][66] , the HLA-B‫-1053ء‬restricted epitope NP [418][419][420][421][422][423][424][425][426] , and the HLA-A‫-1010ء‬restricted epitopes NP [44][45][46][47][48][49][50][51][52] and PB1 591-599 was described previously (5,58).…”

Section: Plasmidsmentioning

confidence: 99%

“…For the epitope M1 [58][59][60][61][62][63][64][65][66] (GILGFVF TL), we performed alanine replacements for each of the nine amino acid positions. In addition, various other amino acid substitutions were introduced in this and four other epitopes, namely the HLA-A‫-1010ء‬restricted epitopes PB1 591-599 and NP [44][45][46][47][48][49][50][51][52] , the HLA-B‫-5072ء‬restricted epitope NP [174][175][176][177][178][179][180][181][182][183][184] , and the HLA-B‫-1053ء‬restricted epitope NP [418][419][420][421][422][423][424][425][426] . Single mutations at anchor residues could result in the loss of the epitopes, which would constitute the most economical way for the virus to escape from immune surveillance by specific CTL.…”

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confidence: 99%

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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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confidence: 97%

Section: Vol 79 2005 Influenza a Virus Epitopes And Escape From Ctlmentioning

confidence: 99%

Section: Plasmidsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…While antibody-mediated selection of variants is the predominant force for evolution of viral strains within a host population, strong evidence is accumulating for the concept that CTLs exert sufficient immunological pressure to drive antigenic variation in MHC class I-restricted CTL epitopes of influenza virus (15,28,31,32). In agreement with this concept, in a previous report utilizing an influenza virus nucleoproteinspecific TCR-transgenic mouse model, we demonstrated selection of CTL escape variant viruses within the lung, indicating that a strong and highly focused CTL response, in combination with the intrinsic genetic variability of influenza virus, is sufficient for CTL-mediated antigenic drift within infected hosts (31).…”

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Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8⁺-T-Cell Escape Variants of Influenza Virus

Price

Huang

et al. 2005

J Virol

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Antigenic variation is a viral strategy exploited to promote survival in the face of the host immune response and represents a major challenge for efficient vaccine development. Influenza viruses are pathogens with high transmissibility and mutation rates, enabling viral escape from immunity induced by prior infection or vaccination. Intense selection from neutralizing antibody drives antigenic changes in the surface glycoproteins, resulting in emergence of new strains able to reinfect hosts immune to previously circulating viruses. CD8 ؉ cytotoxic T cells (CTLs) also provide protective immunity from influenza virus infection and may contribute to the antigenic evolution of influenza viruses. Utilizing mice transgenic for an influenza virus NP366-374 peptide-specific T-cell receptor, we demonstrated that the respiratory tract is a suitable site for generation of escape variants of influenza virus selected by CTL in vivo. In this report the contributions of the perforin and Fas pathways utilized by influenza virus-specific CTLs in viral clearance and selection of CTL escape variants have been evaluated. While transgenic CTLs deficient in either perforin-or Fas-mediated pathways are efficient in initial pulmonary viral control, variant virus emergence was observed in all the mice studied, although the spectrum of viral CTL escape variants selected varied profoundly. Thus, a less-restricted repertoire of escape variants was observed in mice with an intact perforin cytotoxic pathway compared with a limited variant diversity in perforin pathway-deficient mice, although maximal variant diversity was observed in mice having both Fas and perforin pathways intact. We conclude that selection of viral CTL escape variants reflects coordinate action between the tightly controlled perforin/granzyme pathway and the more promiscuous Fas/ FasL pathway.

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High conservation level of CD8⁺ T cell immunogenic regions within an unusual H1N2 human influenza variant

Komadina

Quiñones-Parra

Kedzierska

et al. 2016

Journal of Medical Virology

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Current seasonal influenza vaccines require regular updates due to antigenic drift causing loss of effectiveness and therefore providing little or no protection against novel influenza A subtypes. Next generation vaccines capable of eliciting CD8(+) T cell (CTL) mediated cross-protective immunity may offer a long-term alternative strategy. However, measuring pre- and existing levels of CTL cross-protection in humans is confounded by differences in infection histories across individuals. During 2000-2003, H1N2 viruses circulated persistently in the human population for the first time and we hypothesized that the viral nucleoprotein (NP) contained novel CTL epitopes that may have contributed to the survival of the viruses. This study describes the immunogenic NP peptides of H1N1, H2N2, and H3N2 influenza viruses isolated from humans over the past century, 1918-2003, by comparing this historical dataset to reference NP peptides from H1N2 that circulated in humans during 2000-2003. Observed peptides sequences ranged from highly conserved (15%) to highly variable (12%), with variation unrelated to reported immunodominance. No unique NP peptides which were exclusive to the H1N2 viruses were noted. However, the virus had inherited the NP from a recently emerged H3N2 variant containing novel peptides, which may have assisted its persistence. Any advantage due to this novelty was subsequently lost with emergence of a newer H3N2 variant in 2003. Our approach has potential to provide insight into the population context in which influenza viruses emerge, and may help to inform immunogenic peptide selection for CTL-inducing influenza vaccines. J. Med. Virol. 88:1725-1732, 2016. © 2016 Wiley Periodicals, Inc.

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

Cited by 43 publications

References 18 publications

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

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

Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8⁺-T-Cell Escape Variants of Influenza Virus

High conservation level of CD8⁺ T cell immunogenic regions within an unusual H1N2 human influenza variant

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

Cited by 43 publications

References 18 publications

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

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

Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8+-T-Cell Escape Variants of Influenza Virus

High conservation level of CD8+ T cell immunogenic regions within an unusual H1N2 human influenza variant

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Resources

About

Perforin and Fas Cytolytic Pathways Coordinately Shape the Selection and Diversity of CD8⁺-T-Cell Escape Variants of Influenza Virus

High conservation level of CD8⁺ T cell immunogenic regions within an unusual H1N2 human influenza variant