scholarly journals The Hypervariable Immunodominant NP418-426 Epitope from the Influenza A Virus Nucleoprotein Is Recognized by Cytotoxic T Lymphocytes with High Functional Avidity

2006 ◽  
Vol 80 (12) ◽  
pp. 6024-6032 ◽  
Author(s):  
Adrianus C. M. Boon ◽  
Gerrie de Mutsert ◽  
Ron A. M. Fouchier ◽  
Albert D. M. E. Osterhaus ◽  
Guus F. Rimmelzwaan
Keyword(s):  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Mononuclear Cells ◽  
Influenza Viruses ◽  
Functional Avidity ◽  
Human Virus ◽  
Ctl Epitopes ◽  
Infected Cells

ABSTRACT Recently it was shown that influenza A viruses can accumulate mutations in epitopes associated with escape from recognition by human virus-specific cytotoxic T lymphocytes (CTL). It is unclear what drives diversification of CTL epitopes and why certain epitopes are variable and others remain conserved. It has been shown that simian immunodeficiency virus-specific CTL that recognize their epitope with high functional avidity eliminate virus-infected cells efficiently and drive diversification of CTL epitopes. T-cell functional avidity is defined by the density of major histocompatibility complex class I peptide complexes required to activate specific CTL. We hypothesized that functional avidity of CTL contributes to epitope diversification and escape from CTL also for influenza viruses. To test this hypothesis, the functional avidity of polyclonal CTL populations specific for nine individual epitopes was determined. To this end, peripheral blood mononuclear cells from HLA-A- and -B-genotyped individuals were stimulated in vitro with influenza virus-infected cells to allow expansion of virus-specific CTL, which were used to determine the functional avidity of CTL specific for nine individual epitopes in enzyme-linked immunospot assays. We found that the functional avidity for the respective epitopes varied widely. Furthermore, the functional avidity of CTL specific for the hypervariable NP418-426 epitope was significantly higher than that of CTL recognizing other epitopes (P < 0.01). It was speculated that the high functional avidity of NP418-426-specific CTL was responsible for the diversification of this influenza A virus CTL epitope.

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

2005 ◽  
Vol 79 (17) ◽  
pp. 11239-11246 ◽  
Author(s):  
E. G. M. Berkhoff ◽  
E. de Wit ◽  
M. M. Geelhoed-Mieras ◽  
A. C. M. Boon ◽  
J. Symons ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Amino Acid Substitutions ◽  
Functional Constraints ◽  
Ctl Epitopes

ABSTRACT 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*0201-restricted epitope from the matrix protein, M158-66. 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 M158-66 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.

scholarly journals HLA B37 determines an influenza A virus nucleoprotein epitope recognized by cytotoxic T lymphocytes.

1986 ◽  
Vol 164 (5) ◽  
pp. 1397-1406 ◽  
Author(s):  
A J McMichael ◽  
F M Gotch ◽  
J Rothbard
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Synthetic Peptide ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Human Influenza ◽  
Infected Cells

Human influenza A virus-specific, cytotoxic T cells have been shown previously to recognize the virus nucleoprotein on infected cells. CTL preparations from four HLA B37-positive donors were shown to recognize a synthetic peptide that corresponded to amino acids 335-349 of the nucleoprotein sequence. Influenza-specific CTL from 10 donors of other HLA types failed to recognize this epitope. CD8+ CTL lines were derived from lymphocytes of two HLA B37-positive donors and used to show that the peptide was represented on virus-infected cells and to determine the probable boundaries of the epitope.

scholarly journals Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Marine L. B. Hillaire ◽  
Albert D. M. E. Osterhaus ◽  
Guus F. Rimmelzwaan
Keyword(s):  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Heterosubtypic Immunity

There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8+T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8+T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses.

scholarly journals Cytotoxic T Lymphocytes Established by Seasonal Human Influenza Cross-React against 2009 Pandemic H1N1 Influenza Virus

2010 ◽  
Vol 84 (13) ◽  
pp. 6527-6535 ◽  
Author(s):  
Wenwei Tu ◽  
Huawei Mao ◽  
Jian Zheng ◽  
Yinping Liu ◽  
Susan S. Chiu ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Effector Memory ◽  
Target Cells ◽  
Pandemic H1n1 ◽  
Specific Ctls

ABSTRACT While few children and young adults have cross-protective antibodies to the pandemic H1N1 2009 (pdmH1N1) virus, the illness remains mild. The biological reasons for these epidemiological observations are unclear. In this study, we demonstrate that the bulk memory cytotoxic T lymphocytes (CTLs) established by seasonal influenza viruses from healthy individuals who have not been exposed to pdmH1N1 can directly lyse pdmH1N1-infected target cells and produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). Using influenza A virus matrix protein 1 (M158-66) epitope-specific CTLs isolated from healthy HLA-A2+ individuals, we further found that M158-66 epitope-specific CTLs efficiently killed both M158-66 peptide-pulsed and pdmH1N1-infected target cells ex vivo. These M158-66-specific CTLs showed an effector memory phenotype and expressed CXCR3 and CCR5 chemokine receptors. Of 94 influenza A virus CD8 T-cell epitopes obtained from the Immune Epitope Database (IEDB), 17 epitopes are conserved in pdmH1N1, and more than half of these conserved epitopes are derived from M1 protein. In addition, 65% (11/17) of these epitopes were 100% conserved in seasonal influenza vaccine H1N1 strains during the last 20 years. Importantly, seasonal influenza vaccination could expand the functional M158-66 epitope-specific CTLs in 20% (4/20) of HLA-A2+ individuals. Our results indicated that memory CTLs established by seasonal influenza A viruses or vaccines had cross-reactivity against pdmH1N1. These might explain, at least in part, the unexpected mild pdmH1N1 illness in the community and also might provide some valuable insights for the future design of broadly protective vaccines to prevent influenza, especially pandemic influenza.

scholarly journals Low fidelity assembly of influenza A virus promotes escape from host cells

2018 ◽  
Author(s):  
Michael D. Vahey ◽  
Daniel A. Fletcher
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Phenotypic Variability ◽  
Morphological Variability ◽  
Influenza Viruses ◽  
Host Cells ◽  
Temperature Changes ◽  
Wide Range ◽  
Infected Cells ◽  
Protein Components

AbstractInfluenza viruses inhabit a wide range of host environments using a limited repertoire of protein components. Unlike viruses with stereotyped shapes, influenza produces virions with significant morphological variability even within clonal populations. Whether this tendency to form pleiomorphic virions is coupled to compositional heterogeneity and whether it affects replicative fitness remains unclear. Here we address these questions by developing live strains of influenza A virus amenable to rapid compositional characterization through quantitative, site-specific labeling of viral proteins. Using these strains, we find that influenza A produces virions with broad variations in size and composition from even single infected cells. The virus leverages this phenotypic variability to survive environmental challenges including temperature changes and anti-virals. Complimenting genetic adaptations that act over larger populations and longer times, this ‘low fidelity’ assembly of influenza A virus allows small populations to survive environments that fluctuate over individual replication cycles.

scholarly journals Assessment of the extent of variation in influenza A virus cytotoxic T-lymphocyte epitopes by using virus-specific CD8+ T-cell clones

2007 ◽  
Vol 88 (2) ◽  
pp. 530-535 ◽  
Author(s):  
E. G. M. Berkhoff ◽  
M. M. Geelhoed-Mieras ◽  
R. A. M. Fouchier ◽  
A. D. M. E. Osterhaus ◽  
G. F. Rimmelzwaan
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
T Lymphocyte ◽  
Influenza A ◽  
Matrix Protein ◽  
Cytotoxic T Lymphocyte ◽  
H3n2 Virus ◽  
Human Virus ◽  
Ctl Epitopes ◽  
Cell Clones

The influenza A virus nucleoprotein (NP) and matrix protein are major targets for human virus-specific cytotoxic T-lymphocyte (CTL) responses. Most of the CTL epitopes that have been identified so far are conserved. However, sequence variation in CTL epitopes of the NP has recently been demonstrated to be associated with escape from virus-specific CTLs. To assess the extent of variation in CTL epitopes during influenza A virus evolution, 304 CTL clones derived from six study subjects were obtained with specificity for an influenza A/H3N2 virus isolated in 1981. Subsequently, the frequency of the CTL clones that failed to recognize a more recent influenza virus strain isolated in 2003 was determined. In four of six study subjects, CTLs were found to be specific for variable epitopes, accounting for 2.6 % of all CTL clones. For some of these CTL clones, the minimal epitope and the residues responsible for abrogation of T-cell recognition were identified.

Recognition by HLA-A2-restricted cytotoxic T lymphocytes of endogenously generated and exogenously provided synthetic peptide analogues of the influenza a virus matrix protein

1993 ◽  
Vol 37 (4) ◽  
pp. 252-258 ◽  
Author(s):  
Samir Y. Sauma ◽  
Maureen C. Gammon ◽  
Maria A. Bednarek ◽  
Barry Cunningham ◽  
William E. Biddison ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Influenza A Virus ◽  
Cytotoxic T Lymphocytes ◽  
Synthetic Peptide ◽  
Influenza A ◽  
Matrix Protein ◽  
Peptide Analogues
Sign in / Sign up

Export Citation Format

Share Document