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    ABSTRACT: Evasion of immune T cell responses is crucial for persistent viruses to establish normal carrier state. Most studies on active immune modulation mechanisms have focused on the virus production stage of the infected cells when large number of viral antigens, and potential immune-modulators, are expressed. For oncogenic viruses such as KSHV, which is carried as lifelong infections usually with little harmful effect but can cause various tumours, the immune evasion strategies can also be relevant in the context of tumourigenesis. In this study, we report that the vIRF3 latent viral gene expressed in KSHV-related tumours functions as a potent immunevasin. Expression of vIRF3 down-regulates surface MHC-II DR expression with a slow kinetics but, more importantly can substantially inhibit the recognition by KSHV-specific CD4 T cells prior to its effects on MHC-II DR down-regulation in model cell systems. This property of vIRF3 is only partly due to its ability to inhibit the transcription of CIITA, and thus MHC-II expression; CIITA-independent inhibition of MHC-II transccripts and another as yet unidentified post-transcriptional mechanism are also involved in qualitatively modulating the availability of specific peptide/MHC-II complexes at the cell surface. Consistent with these observations, the vIRF3 expressing KSHV-associated PEL lines are generally resistant to recognition by KSHV-specific CD4 T cells. Interestingly, some PEL lines exhibit small subpopulations with lower vIRF3 expression that can be recognized. These data implicate vIRF3 as a critical determinant of the MHC-II antigen presentation function in KSHV-associated PEL that is likely to be important in the pathogenesis of these tumours.
    Full-text · Article · Feb 2013 · Journal of Virology
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    ABSTRACT: Lifelong persistent infection by herpesviruses depends on the balance between host immune responses and viral immune evasion. CD4 T cells responding to antigens presented on major histocompatibility complex class II (MHC-II) molecules are known to play an important role in controlling herpesvirus infections. Here we review, with emphasis on human herpesvirus infections, the strategies evolved to evade CD4 T cell immunity. These viruses target multiple points on the MHC class II antigen presentation pathway. The mechanisms include: suppression of CIITA to inhibit the synthesis of MHC class II molecules, diversion or degradation of HLA-DR molecules during membrane transport, and direct targeting of the invariant chain chaperone of HLA-DR.
    Full-text · Article · Aug 2012 · Viruses
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    ABSTRACT: Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral interference with MHC-II antigen presentation is less well understood, not only for EBV but also for other persistent viruses. Here we show that the EBV encoded BZLF1 can interfere with recognition by immune CD4+ effector T cells. This impaired T cell recognition occurred in the absence of a reduction in the expression of surface MHC-II, but correlated with a marked downregulation of surface CD74 on the target cells. Furthermore, impaired CD4+ T cell recognition was also observed with target cells where CD74 expression was downregulated by shRNA-mediated inhibition. BZLF1 downregulated surface CD74 via a post-transcriptional mechanism distinct from its previously reported effect on the CIITA promoter. In addition to being a chaperone for MHC-II αβ dimers, CD74 also functions as a surface receptor for macrophage Migration Inhibitory Factor and enhances cell survival through transcriptional upregulation of Bcl-2 family members. The immune-evasion function of BZLF1 therefore comes at a cost of induced toxicity. However, during EBV lytic cycle induced by BZLF1 expression, this toxicity can be overcome by expression of the vBcl-2, BHRF1, at an early stage of lytic infection. We conclude that by inhibiting apoptosis, the vBcl-2 not only maintains cell viability to allow sufficient time for synthesis and accumulation of infectious virus progeny, but also enables BZLF1 to effect its immune evasion function.
    Full-text · Article · Dec 2011 · PLoS Pathogens
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