Interference with T cell receptor–HLA-DR interactions by Epstein–Barr virus gp42 results in reduced T helper cell recognition

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Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV− and EBV+ human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses.

Section: Discussionmentioning

confidence: 99%

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

Gent

Griffin

Berkhoff

et al. 2011

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“…Human papillomavirus 16 E5 protein perturbs MHC class II maturation by inhibiting the degradation of invariant chain (32). EBV gp42 impairs T cell activation by binding to HLA class II molecules and blocking TCR engagement (33). Lymphocytic choriomeningitis virus interferes with DC maturation and Ag-presenting activity by reducing the surface expression of MHC class I, MHC class II, CD40, CD80, and CD86 molecules (42).…”

Section: Discussionmentioning

confidence: 99%

Disruption of MHC Class II-Restricted Antigen Presentation by Vaccinia Virus

Wang

Zhou

et al. 2005

Vaccinia virus (VV), currently used in humans as a live vaccine for smallpox, can interfere with host immunity via several discrete mechanisms. In this study, the effect of VV on MHC class II-mediated Ag presentation was investigated. Following VV infection, the ability of professional and nonprofessional APC to present Ag and peptides to CD4+ T cells was impaired. Viral inhibition of class II Ag presentation could be detected within 1 h, with diminished T cell responses dependent upon the duration of APC infection and virus titer. Exposure of APC to replication-deficient virus also diminished class II Ag presentation. Virus infection of APC perturbed Ag presentation by newly synthesized and recycling class II molecules, with disruptions in both exogenous and cytoplasmic Ag presentation. Virus-driven expression of an endogenous Ag, failed to restore T cell responsiveness specific for this Ag in the context of MHC class II molecules. Yet, both class II protein steady-state and cell surface expression were not altered by VV. Biochemical and functional analysis revealed that VV infection directly interfered with ligand binding to class II molecules. Together, these observations suggest that disruption of MHC class II-mediated Ag presentation may be one of multiple strategies VV has evolved to escape host immune surveillance.

“…The following Abs have been used in this study and, unless otherwise indicated, were described elsewhere (19,(25)(26)(27). OX34 (American Tissue Culture Collection) is a mouse IgG2a mAb specific for the extracellular domain of rat CD2.…”

Section: Antibodiesmentioning

confidence: 99%

“…SDS-PAGE and immunoblotting were performed as reported previously (19). Briefly, total postnuclear Nonidet P-40 cell lysates were denatured in reducing sample buffer (final concentration: 2% SDS, 50 mM Tris-HCl, pH 8.0, 10% glycerol, 5% 2-ME, 0.05% bromphenol blue) and solubilized proteins equivalent to 2 ϫ 10 5 cells were separated by 10% SDS-PAGE and transferred to polyvinylidene difluoride membranes (Amersham Biosciences).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Indeed, immune evasive functions have been ascribed to a number of EBV lytic cycle proteins, including an IL-10 homologue (16), a putative viral soluble receptor for CSF-1 (17), and an inhibitor of IFN-␥ receptor expression (18). In addition, the late BZLF2 gene product, gp42, interferes with CD4 ϩ T cell responses by associating with HLA class II, causing steric hindrance of TCR recognition of peptide-HLA complexes (19). Thus, some potential immunoevasins have been identified for EBV, but the picture is by no means complete and their contribution to avoidance of immune detection during natural infection remains to be evaluated.…”

mentioning

confidence: 99%

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Impaired Transporter Associated with Antigen Processing-Dependent Peptide Transport during Productive EBV Infection

Ressing

Keating

Leeuwen

et al. 2005

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103

Human herpesviruses, including EBV, persist for life in infected individuals. During the lytic replicative cycle that is required for the production of infectious virus and transmission to another host, many viral Ags are expressed. Especially at this stage, immune evasion strategies are likely to be advantageous to avoid elimination of virus-producing cells. However, little is known about immune escape during productive EBV infection because no fully permissive infection model is available. In this study, we have developed a novel strategy to isolate populations of cells in an EBV lytic cycle based on the expression of a reporter gene under the control of an EBV early lytic cycle promoter. Thus, induction of the viral lytic cycle in transfected EBV+ B lymphoma cells resulted in concomitant reporter expression, allowing us, for the first time, to isolate highly purified cell populations in lytic cycle for biochemical and functional studies. Compared with latently infected B cells, cells supporting EBV lytic cycle displayed down-regulation of surface HLA class I, class II, and CD20, whereas expression levels of other surface markers remained unaffected. Moreover, during lytic cycle peptide transport into the endoplasmic reticulum, was reduced to <30% of levels found in latent infection. Because steady-state levels of TAP proteins were unaffected, these results point toward EBV-induced interference with TAP function as a specific mechanism contributing to the reduced levels of cell surface HLA class I. Our data implicate that EBV lytic cycle genes encode functions to evade T cell recognition, thereby creating a window for the generation of viral progeny.