RESUMEN
Kaposi's sarcoma-associated herpesvirus encodes four genes with homology to the family of interferon regulatory factors (IRFs). At least one of these viral IRFs, vIRF-3, is expressed in latently Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma (PEL) cells and is essential for the survival of PEL cells. We now report that vIRF-3 interacts with cellular IRF-5, thereby inhibiting binding of IRF-5 to interferon-responsive promoter elements. Consequently, vIRF-3 blocked IRF-5-mediated promoter activation. A central double helix motif present in vIRF-3 was sufficient to abrogate both DNA binding and transcriptional transactivation by IRF-5. Upon DNA damage or activation of the interferon or Toll-like receptor pathways, cytoplasmic IRF-5 has been reported to be translocated to the nucleus, which results in induction of both p53-independent apoptosis and p21-mediated cell cycle arrest. We report here that IRF-5 is present in the nuclei of PEL cells without interferon stimulation. Silencing of vIRF-3 expression in PEL cells was accompanied by increased sensitivity to interferon-mediated apoptosis and up-regulation of IRF-5 target genes. In addition, vIRF-3 antagonized IRF-5-mediated activation of the p21 promoter. The data presented here indicate that vIRF-3 contributes to immune evasion and sustained proliferation of PEL cells by releasing IRF-5 from transcription complexes.
Asunto(s)
Núcleo Celular/metabolismo , Herpesvirus Humano 8/metabolismo , Factores Reguladores del Interferón/metabolismo , Elementos de Respuesta , Proteínas Virales/metabolismo , Transporte Activo de Núcleo Celular/genética , Transporte Activo de Núcleo Celular/inmunología , Secuencias de Aminoácidos/genética , Secuencias de Aminoácidos/inmunología , Apoptosis/genética , Apoptosis/inmunología , Núcleo Celular/genética , Núcleo Celular/inmunología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/inmunología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Silenciador del Gen , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/inmunología , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Linfoma de Efusión Primaria/genética , Linfoma de Efusión Primaria/inmunología , Linfoma de Efusión Primaria/metabolismo , Unión Proteica/genética , Unión Proteica/inmunología , Receptores de Interferón/genética , Receptores de Interferón/inmunología , Receptores de Interferón/metabolismo , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Activación Transcripcional/genética , Activación Transcripcional/inmunología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Proteínas Virales/genética , Proteínas Virales/inmunologíaRESUMEN
A promising approach to protect susceptible individuals against severe diseases is the inoculation of plasmids. Such DNA vaccines against influenza virus infections were quite efficient in different animal models; but still this procedure is not in clinical use until today. The present study reports the generation and characterization of bicistronic plasmids which enables the expression of influenza A virus gene sequences together with immunostimulatory cytokines demonstrating that among these cytokines especially interleukin-2 (IL-2) was efficient to prevent a lethal influenza virus infection in mice.
