RESUMEN
We isolated a UL13 gene-deleted mutant of the herpes simplex virus type 1 (HSV-1) strain VR3 (VRDelta13) and its revertant virus (VRDelta13R). This deletion mutant still had virus host shutoff (vhs) activity, although a previous report had suggested the possibility of a functional relation between the UL13 product, that is protein kinase (PK), and vhs activity. We compared the in vivo growth of these viruses in BALB/c mice. VRDelta13 was cleared in the early period of intraperitoneal infection. VRDelta13 had a higher sensitivity to the mouse type I interferon (IFN) and showed a higher level of IFN induction in the study period of infection than did VR3 and VRDelta13R. These results suggest that a nonspecific antiviral response (i.e., the IFN system) may contribute to this rapid inhibition of viral replication in vivo.
Asunto(s)
Eliminación de Gen , Genes Virales/genética , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidad , Interferón Tipo I/fisiología , Proteínas Quinasas/genética , Proteínas Estructurales Virales/genética , Células 3T3 , Animales , Línea Celular , Chlorocebus aethiops , Modelos Animales de Enfermedad , Resistencia a Medicamentos/inmunología , Femenino , Herpes Simple/mortalidad , Herpesvirus Humano 1/enzimología , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Interferón Tipo I/biosíntesis , Dosificación Letal Mediana , Ratones , Ratones Endogámicos BALB C , Especificidad por Sustrato/genética , Células Vero , Ensayo de Placa Viral , Virulencia , Replicación Viral/genéticaRESUMEN
To clarify whether varicella-zoster virus (VZV) protein kinase (PK; ORF47) takes part in phosphorylation of anti-herpesvirus nucleosides, thymidine kinase (TK) deficient, and PK/TK double deficient recombinant VZV strains were isolated and their susceptibility, and that of wild type and PK-deficient strains to various nucleoside analogs was evaluated. The PK-deficient VZV strains showed a sensitivity equal to that of the wild type strain against all compounds tested, including ganciclovir. This indicates that PK is not involved in phosphorylation of the tested nucleosides in VZV-infected cells.
Asunto(s)
Antivirales/farmacología , Herpesvirus Humano 3/efectos de los fármacos , Herpesvirus Humano 3/enzimología , Nucleósidos/farmacología , Proteínas Quinasas/metabolismo , Antivirales/metabolismo , Células Cultivadas , Herpesvirus Humano 3/genética , Humanos , Nucleósidos/metabolismo , Fosforilación , Proteínas Quinasas/genética , Timidina Quinasa/metabolismo , Ensayo de Placa ViralRESUMEN
The UL41 gene product (vhs) of herpes simplex virus (HSV) is packaged in the virion, and mediates host protein synthesis shutoff at the early stage of the virus replication cycle. In order to clarify the role of vhs in virus replication and virulence, we isolated a completely UL41-deficient mutant (the VRDelta41 strain) and its revertant (the VRDelta41R strain). In the mouse encephalitis model, the replication of strain VRDelta41 was inhibited after 2 days post-infection, resulting in low virulence, by gamma-ray-sensitive cells such as lymphocytes and/or neutrophils. The result suggested that some cytokines, produced in VRDelta41-inoculated brains, activate and induce the migration of gamma-ray-sensitive cells to the infection site. Therefore, cytokines produced by HSV-1-infected human cells were screened, and potent inductions of interleukin (IL)-1beta, IL-8 and macrophage inflammatory protein-1alpha by VRDelta41 infection were observed. Moreover, the VRDelta41 strain showed 20- and 5-fold higher sensitivity to interferon-alpha and -beta compared to the wild-type strain, respectively. These results indicate that one important role of vhs in vivo is evasion from non-specific host defence mechanisms during primary infection through suppression of cytokine production in HSV-infected cells and reduction of the anti-HSV activity of interferon-alpha and -beta.
Asunto(s)
Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Proteínas Virales/genética , Animales , Citocinas/biosíntesis , Citocinas/genética , Femenino , Herpesvirus Humano 1/efectos de los fármacos , Humanos , Inmunidad Innata , Interferones/farmacología , Ratones , Ratones Endogámicos BALB C , Ribonucleasas , Células U937 , Proteínas Virales/fisiología , VirulenciaRESUMEN
Normal mice inoculated intravenously with 50 microg trehalose-6,6'-dimycolate, a glycolipid component of the cell wall of Mycobacterium, in an oil-in-water emulsion (TDM emulsion) acquired a high resistance to intranasal lethal infection of an influenza virus. In contrast, TDM emulsion-treated T-cell receptor delta gene mutant (TCR delta-/-) mice acquired insufficient resistance against the lethal influenza virus infection. The patterns of insufficient resistance were identical to the results obtained previously with mice which were depleted of T-lymphocytes bearing gammadelta T-cell receptors (gammadelta T-cells) by in vivo administration of anti-gammadelta T-cell receptor monoclonal antibody (Hoq et al, J. Gen. Virol. 78: 1597-1603, 1997). These results strongly suggest that the gammadelta T-cells play an important non-specific role in resistance against influenza virus infection.