Azidothymidine sensitizes primary effusion lymphoma cells to Kaposi sarcoma-associated herpesvirus-specific CD4+ T cell control and inhibits vIRF3 function: AZT sensitizes PELs to KSHV-specific CD4+ T cell control

Research output: Contribution to journalArticlepeer-review

Standard

Azidothymidine sensitizes primary effusion lymphoma cells to Kaposi sarcoma-associated herpesvirus-specific CD4+ T cell control and inhibits vIRF3 function : AZT sensitizes PELs to KSHV-specific CD4+ T cell control. / Williamson, Samantha; Nicol, Samantha; Sturzl, Michael; Sabbah, Shereen; Hislop, Andrew.

In: PLoS pathogens, Vol. 12, No. 11, e1006042, 28.11.2016.

Research output: Contribution to journalArticlepeer-review

Harvard

APA

Vancouver

Author

Bibtex

@article{5932d0a56a8140e0a74abf2e5177fbbf,
title = "Azidothymidine sensitizes primary effusion lymphoma cells to Kaposi sarcoma-associated herpesvirus-specific CD4+ T cell control and inhibits vIRF3 function: AZT sensitizes PELs to KSHV-specific CD4+ T cell control",
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.",
keywords = "Cancer, CD4 T cell, Kaposi's sarcoma-associated herpesvirus, Immune Evasion, Apoptosis",
author = "Samantha Williamson and Samantha Nicol and Michael Sturzl and Shereen Sabbah and Andrew Hislop",
year = "2016",
month = nov,
day = "28",
doi = "10.1371/journal.ppat.1006042",
language = "English",
volume = "12",
journal = "PLoS pathogens",
issn = "1553-7366",
publisher = "Public Library of Science (PLOS)",
number = "11",

}

RIS

TY - JOUR

T1 - Azidothymidine sensitizes primary effusion lymphoma cells to Kaposi sarcoma-associated herpesvirus-specific CD4+ T cell control and inhibits vIRF3 function

T2 - AZT sensitizes PELs to KSHV-specific CD4+ T cell control

AU - Williamson, Samantha

AU - Nicol, Samantha

AU - Sturzl, Michael

AU - Sabbah, Shereen

AU - Hislop, Andrew

PY - 2016/11/28

Y1 - 2016/11/28

N2 - 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.

AB - 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.

KW - Cancer

KW - CD4 T cell

KW - Kaposi's sarcoma-associated herpesvirus

KW - Immune Evasion

KW - Apoptosis

U2 - 10.1371/journal.ppat.1006042

DO - 10.1371/journal.ppat.1006042

M3 - Article

VL - 12

JO - PLoS pathogens

JF - PLoS pathogens

SN - 1553-7366

IS - 11

M1 - e1006042

ER -