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Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+) T-cell responses to internal proteins, hemagglutinins, and neuraminidases.

ABSTRACT: We performed a genome-wide screening for T-cell epitopes using synthetic peptides that encompass all of the influenza A viral proteins, including subtype variants for hemagglutinin (HA; H1, H3, and H5) and neuraminidase (NA; human and avian N1 and N2) proteins, based on the sequence information of recently circulating strains. We identified a total of 83 peptides, 54 of them novel, to which specific T cells were detectable in interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot assays using peripheral blood mononuclear cells from four healthy adult donors. The surface glycoproteins, HA and NA, major components of vaccines, expressed many T-cell epitopes. HA and matrix protein 1 expressed more T-cell epitopes than other viral proteins, most of which were recognized by CD4(+) T cells. We established several cytotoxic CD4(+) T-cell lines from these donors. We also analyzed H1 and H3 HA-specific T-cell responses using the peripheral blood mononuclear cells of 30 hospital workers. Fifty-three percent of donors gave a positive response to H3 HA peptides, whereas 17% gave a positive response to H1 HA peptides. Our genome-wide screening is useful in identifying T-cell epitopes and is complementary to the approach based on the predicted binding peptides to well-studied HLA-A, -B, and -DR alleles.

SUBMITTER: Babon JA

PROVIDER: S-EPMC2767101 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+) T-cell responses to internal proteins, hemagglutinins, and neuraminidases.

Babon Jenny Aurielle B JA Cruz John J Orphin Laura L Pazoles Pamela P Co Mary Dawn T MD Ennis Francis A FA Terajima Masanori M

Human immunology 20090611 9

We performed a genome-wide screening for T-cell epitopes using synthetic peptides that encompass all of the influenza A viral proteins, including subtype variants for hemagglutinin (HA; H1, H3, and H5) and neuraminidase (NA; human and avian N1 and N2) proteins, based on the sequence information of recently circulating strains. We identified a total of 83 peptides, 54 of them novel, to which specific T cells were detectable in interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot assays u ...[more]

PMID: 19524006

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Project description:BACKGROUND:With the emergence of new influenza virus strains that are resistant to current inhibitors such as oseltamivir (anti-neuraminidase (NA)) and amantadine (anti-M2 proton channel), influenza A viruses continue to be a serious threat to the public health worldwide. With this in view, there is a persistent need for the development of broader and more effective vaccines and therapeutics. Identification of broadly neutralizing antibodies (bNAbs) that recognize relatively invariant structures ?on influenza haemagglutinin (HA) stem has invigorated efforts to develop universal influenza vaccines. AIM:The current computational study is designed to identify potential flavonoid inhibitors that bind to the contact epitopes of HA stem that are targeted by broadly neutralizing antibodies (bNAb). METHOD:In this study, we utilized the three-dimensional crystallographic structure of different HA subtypes (H1, H2, H5, H3, and H7) in complex with bNAb to screen for potential broadly reactive influenza inhibitors. We performed Quantitative Structure-Activity and Relationship (QSAR) for 100 natural compounds known for their antiviral activity and performed molecular docking using AutoDock 4.2 suite. Furthermore, we conducted virtual screening of 1413 bioassay hit compounds by using virtual lab bench CLC Drug Discovery. RESULTS:The results showed 18 lead flavonoids with strong binding abilities to bNAb epitopes of various HA subtypes. These 18 broadly reactive compounds exhibited significant interactions with an average of seven Hbonds, docking energy of -22.43 kcal·mol-1, and minimum interaction ? energy of -4.65 kcal·mol-1, with functional contact residues. Procyanidin depicted strong interactions with group 1 HAs, whereas both sorbitol and procyanidin exhibited significant interactions with group 2 HAs. CONCLUSION:Using in silico docking analysis, we identified 18 bioactive flavonoids with potential strong binding cababilities to influenza HA-stems of various subtypes, which are the target for bNAb. The virtual screened bioassay hit compounds depicted a high number of Hbonds but low interaction and docking values compared to antiviral flavonoids. Using structure-based design and nanotechnology-based approaches, identified molecules could be modified to generate next generation anti-influenza drugs.

Dataset Information

Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+) T-cell responses to internal proteins, hemagglutinins, and neuraminidases.

Publications

Genome-wide screening of human T-cell epitopes in influenza A virus reveals a broad spectrum of CD4(+) T-cell responses to internal proteins, hemagglutinins, and neuraminidases.

Similar Datasets

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