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. 2008 Jun;82(11):5161-6.
doi: 10.1128/JVI.02694-07. Epub 2008 Mar 19.

Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus

J H C M Kreijtz  1 , G de Mutsert, C A van Baalen, R A M Fouchier, A D M E Osterhaus, G F Rimmelzwaan
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Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus

J H C M Kreijtz et al. J Virol. 2008 Jun.

Abstract

Since the number of human cases of infection with avian H5N1 influenza viruses is ever increasing, a pandemic outbreak caused by these viruses is feared. Therefore, in addition to virus-specific antibodies, there is considerable interest in immune correlates of protection against these viruses, which could be a target for the development of more universal vaccines. After infection with seasonal influenza A viruses of the H3N2 and H1N1 subtypes, individuals develop virus-specific cytotoxic T-lymphocyte responses, which are mainly directed against the relatively conserved internal proteins of the virus, like the nucleoprotein (NP). Virus-specific cytotoxic T lymphocytes (CTL) are known to contribute to protective immunity against infection, but knowledge about the extent of cross-reactivity with avian H5N1 influenza viruses is sparse. In the present study, we evaluated the cross-reactivity with H5N1 influenza viruses of polyclonal CTL obtained from a group of well-defined HLA-typed study subjects. To this end, the recognition of synthetic peptides representing H5N1 analogues of known CTL epitopes was studied. In addition, the ability of CTL specific for seasonal H3N2 influenza virus to recognize the NP of H5N1 influenza virus or H5N1 virus-infected cells was tested. It was concluded that, apart from some individual epitopes that displayed amino acid variation between H3N2 and H5N1 influenza viruses, considerable cross-reactivity exists with H5N1 viruses. This preexisting cross-reactive T-cell immunity in the human population may dampen the impact of a next pandemic.

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Figures

FIG. 1.
FIG. 1.
The presence of known CTL epitopes in H5N1 strains. The percentage of H5N1 viruses with an epitope sequence identical to human influenza viruses (white bars) is shown. The black bars indicate the percentage of H5N1 viruses with one or more amino acid substitutions in the epitope sequence. The absolute numbers of each variant of an epitope are shown in panel B, where each color represents a single variant (sequences can be found in Table 1). For this analysis almost 900 H5N1 viruses for which sequence information was available in the influenza sequence database (12) were analyzed.
FIG. 2.
FIG. 2.
Epitope-specific IFN-γ production by CTLs after stimulation with peptide-pulsed BLCL. The number of IFN-γ-producing cells per 10,000 CD8+ T cells (5,000 cells for subject 3) from subjects from HLA groups I (A), II (B), and III (C) were measured by ELISPOT assay. CD8+ T cells were isolated from PBMC populations expanded in vitro with influenza virus A/NL/18/94 and subsequently stimulated with peptide variants as indicated. (*, peptide sequence of the known human influenza virus CTL epitopes).
FIG. 3.
FIG. 3.
Recognition of NP derived from H3N2 and H5N1 influenza virus by in vitro expanded PBMC specific for influenza virus A/NL/18/94 (H3N2). The lytic activity of in vitro expanded PBMC was tested with MHC-I matched BLCL nucleofected with NP-GFP coding plasmid (NP of either influenza virus A/NL/18/94 [black circles] or A/VN/1194/04 [open circles]) or empty control GFP plasmid (gray circles). The NP-specific lytic activity was tested with PBMC of the subjects from group I (subjects 1 to 4), II (subjects 5 to 9), and III (subjects 10 to 14 and 16). E:T ratios were 0, 3.125, 6.25, 12.5, 25, and 50 for all subjects except numbers 13 and 14, for whom E:T ratios were 0, 0.3, 1, 3, 10 and 30. The lytic activities against control plasmid-transfected target cells are not visible for subjects 13 and 14 as a result of negative values for the percentages of specific lysis, which were caused by slight increases in the number of GFP-positive viable cells. Standard deviation of the means was <10%.
FIG. 4.
FIG. 4.
Recognition of influenza virus-infected BLCL by CTLs. The number of IFN-γ-producing cells per 10,000 CD8+ T cells was measured by ELISPOT assay after stimulation with BLCL infected with influenza virus A/NL/18/94 or A/VN/1194/04. Each symbol represents an individual subject from group I (A), II (B), or III (C). Uninfected BLCL were used as negative controls. The horizontal bars represent the average responses of all study subjects in groups I, II, and III.
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