RESUMO
Respiratory syncytial virus (RSV) is the most common cause of serious viral bronchiolitis in infants, young children, and the elderly. Currently, there is not an FDA-approved vaccine available for RSV, though the mAb palivizumab is licensed to reduce the incidence of RSV disease in premature or at-risk infants. The palivizumab epitope is a well-characterized, approximately 24-aa helix-loop-helix structure on the RSV fusion (F) protein (F254-277). Here, we genetically inserted this epitope and multiple site variants of this epitope within a versatile woodchuck hepadnavirus core-based virus-like particle (WHcAg-VLP) to generate hybrid VLPs that each bears 240 copies of the RSV epitope in a highly immunogenic arrayed format. A challenge of such an epitope-focused approach is that to be effective, the conformational F254-277 epitope must elicit antibodies that recognize the intact virus. A number of hybrid VLPs containing RSV F254-277 were recognized by palivizumab in vitro and elicited high-titer and protective neutralizing antibody in rodents. Together, the results from this proof-of-principle study suggest that the WHcAg-VLP technology may be an applicable approach to eliciting a response to other structural epitopes.
Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Antígenos Virais/imunologia , Epitopos Imunodominantes/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sinciciais Respiratórios/imunologia , Proteínas Virais de Fusão/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Técnicas de Química Combinatória , Microscopia Crioeletrônica , Ensaio de Imunoadsorção Enzimática , Sequências Hélice-Alça-Hélice/imunologia , Vírus da Hepatite B da Marmota/genética , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Palivizumab , Conformação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/imunologia , Sigmodontinae , Vacinação , Vacinas de Partículas Semelhantes a Vírus , Proteínas Virais de Fusão/químicaRESUMO
Regulatory T (Treg) cells represent one of the main mechanisms of regulating self-reactive immune cells. Treg cells are thought to play a role in down-regulating immune responses to self or allogeneic antigens in the periphery. Although the function of Treg cells has been demonstrated in many experimental settings, the precise mechanisms and antigen specificity often remain unclear. In a hepatitis B e antigen-T-cell receptor (HBeAg-TCR) double transgenic mouse model, we observed a phenotypically unique (TCR+) CD4- /CD8- CD25(+/-) GITR(high) PD-1(high) FoxP3-) HBeAg-specific population that demonstrates immune regulatory function. This HBeAg-specific double-negative regulatory cell population proliferates vigorously in vitro, in contrast to any other known regulatory population, in an interleukin-2-independent manner.