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.