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Azidothymidine Sensitizes Primary Effusion Lymphoma Cells to Kaposi Sarcoma-Associated Herpesvirus-Specific CD4+ T Cell Control and Inhibits vIRF3 Function.
Williamson, Samantha J; Nicol, Samantha M; Stürzl, Michael; Sabbah, Shereen; Hislop, Andrew D.
Afiliação
  • Williamson SJ; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
  • Nicol SM; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
  • Stürzl M; Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
  • Sabbah S; Department of Immunobiology, King's College London, London, United Kingdom.
  • Hislop AD; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
PLoS Pathog ; 12(11): e1006042, 2016 Nov.
Article em En | MEDLINE | ID: mdl-27893813
ABSTRACT
Kaposi sarcoma-associated herpesvirus (KSHV) is linked with the development of Kaposi sarcoma and the B lymphocyte disorders primary effusion lymphoma (PEL) and multi-centric Castleman disease. T cell immunity limits KSHV infection and disease, however the virus employs multiple mechanisms to inhibit efficient control by these effectors. Thus KSHV-specific CD4+ T cells poorly recognize most PEL cells and even where they can, they are unable to kill them. To make KSHV-infected cells more sensitive to T cell control we treated PEL cells with the thymidine analogue azidothymidine (AZT), which sensitizes PEL lines to Fas-ligand and TRAIL challenge; effector mechanisms which T cells use. PELs co-cultured with KSHV-specific CD4+ T cells in the absence of AZT showed no control of PEL outgrowth. However in the presence of AZT PEL outgrowth was controlled in an MHC-restricted manner. To investigate how AZT sensitizes PELs to immune control we first examined BJAB cells transduced with individual KSHV-latent genes for their ability to resist apoptosis mediated by stimuli delivered through Fas and TRAIL receptors. This showed that in addition to the previously described vFLIP protein, expression of vIRF3 also inhibited apoptosis delivered by these stimuli. Importantly vIRF3 mediated protection from these apoptotic stimuli was inhibited in the presence of AZT as was a second vIRF3 associated phenotype, the downregulation of surface MHC class II. Although both vFLIP and vIRF3 are expressed in PELs, we propose that inhibiting vIRF3 function with AZT may be sufficient to restore T cell control of these tumor cells.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Proteínas Virais / Linfócitos T CD4-Positivos / Zidovudina / Evasão Tumoral / Fatores Reguladores de Interferon / Linfoma de Efusão Primária Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Revista: PLoS Pathog Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Proteínas Virais / Linfócitos T CD4-Positivos / Zidovudina / Evasão Tumoral / Fatores Reguladores de Interferon / Linfoma de Efusão Primária Tipo de estudo: Risk_factors_studies Limite: Humans Idioma: En Revista: PLoS Pathog Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Reino Unido