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1.
Proteins ; 81(10): 1759-75, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23625724

RESUMO

The conserved "stem" domain of influenza virus hemagglutinin (HA) is a target for broadly neutralizing antibodies and a potential vaccine antigen for induction of hetero-subtypic protection. The epitope of 12D1, a previously reported bnAb neutralizing several H3 subtype influenza strains, was putatively mapped to residues 76-106 of the CD-helix, also referred to as long alpha helix (LAH) of the HA stem. A peptide derivative consisting of wt-LAH residues 76-130 conjugated to keyhole limpet hemocyanin was previously shown to confer robust protection in mice against challenge with influenza strains of subtypes H3, H1, and H5 which motivated the present study. We report the design of multiple peptide derivatives of LAH with or without heterologous trimerization sequences and show that several of these are better folded than wt-LAH. However, in contrast to the previous study immunization of mice with wt-LAH resulted in negligible protection against a lethal homologous virus challenge, while some of the newly designed immunogens could confer weak protection. Combined with structural analysis of HA, our data suggest that in addition to LAH, other regions of HA are likely to significantly contribute to the epitope for 12D1 and will be required to elicit robust protection. In addition, a dynamic, flexible conformation of isolated LAH peptide may be required for eliciting a functional anti-viral response.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H3N2 , Sequência de Aminoácidos , Animais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vacinas contra Influenza/química , Vacinas contra Influenza/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Dados de Sequência Molecular , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Estrutura Secundária de Proteína , Subunidades Proteicas , Análise de Sobrevida
2.
Virology ; 321(1): 134-43, 2004 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-15033572

RESUMO

Data from human studies and animal experiments indicate a dominant role of T-cells over antibodies in controlling acute Lassa virus infection and providing immunity to reinfection. Knowledge of the epitopes recognized by T-cells may therefore be crucial to the development of a recombinant Lassa virus vaccine. In order to study human T-cell reactivity to the most conserved structural protein of Lassa virus, the glycoprotein 2 (GP2), seven GP2-specific CD4+ T-cell clones (TCCs) were generated from the lymphocytes of a Lassa antibody positive individual. All TCC displayed high specific proliferation, showed DR-restriction, and produced IFN-gamma upon stimulation with recombinant GP2. The epitope of four of the clones was localized to a short stretch of 13 amino acids located in the N-terminal part of GP2 (aa 289-301, numbering according to sequence of GPC). This epitope is conserved in all strains of Lassa virus and lymphocytic choriomeningitis virus (LCMV), shows >90% similarity in all New World arenaviruses of clade B, and overlaps with the proposed fusion domain of GP2. Peptides with conservative aa exchanges, as they naturally occur in the epitope 289-301 of the Old World arenavirus Mopeia and some New World arenaviruses, continued to effectively stimulate the Lassa-GP2-specific T-cell clones tested. The finding of a human T-helper cell epitope, which is highly conserved between Old and New World arenaviruses, is of importance for the design of arenavirus vaccines.


Assuntos
Arenavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Glicoproteínas/imunologia , Proteínas do Envelope Viral/imunologia , Sequência de Aminoácidos , Arenavirus/genética , Doadores de Sangue , Divisão Celular , Células Clonais , Mapeamento de Epitopos , Epitopos de Linfócito T/genética , Feminino , Glicoproteínas/genética , Humanos , Vírus Lassa/genética , Vírus Lassa/imunologia , Masculino , Dados de Sequência Molecular , Peptídeos/genética , Peptídeos/farmacologia , Alinhamento de Sequência , Especificidade da Espécie , Proteínas do Envelope Viral/genética
3.
J Virol ; 77(19): 10700-5, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12970458

RESUMO

Lassa virus is an enveloped virus with glycoprotein spikes on its surface. It contains an RNA ambisense genome that encodes the glycoprotein precursor GP-C, the nucleoprotein NP, the polymerase L, and the Z protein. Here we demonstrate that the Lassa virus Z protein (i). is abundant in viral particles, (ii). is strongly membrane associated, (iii). is sufficient in the absence of all other viral proteins to release enveloped particles, and (iv). contains two late domains, PTAP and PPXY, necessary for the release of virus-like particles. Our data provide evidence that Z is the Lassa virus matrix protein that is the driving force for virus particle release.


Assuntos
Vírus Lassa/fisiologia , Proteínas da Matriz Viral/fisiologia , Vírion/fisiologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Proteínas de Transporte/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular , Dados de Sequência Molecular , Proteínas da Matriz Viral/análise , Proteínas da Matriz Viral/química
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