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The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface.

ABSTRACT: The Herpes Simplex Virus 1 (HSV-1) glycoprotein gE-gI is a transmembrane Fc receptor found on the surface of infected cells and virions that binds human immunoglobulin G (hIgG). gE-gI can also participate in antibody bipolar bridging (ABB), a process by which the antigen-binding fragments (Fabs) of the IgG bind a viral antigen while the Fc binds to gE-gI. IgG Fc binds gE-gI at basic, but not acidic, pH, suggesting that IgG bound at extracellular pH by cell surface gE-gI would dissociate and be degraded in acidic endosomes/lysosomes if endocytosed. The fate of viral antigens associated with gE-gI-bound IgG had been unknown: they could remain at the cell surface or be endocytosed with IgG. Here, we developed an in vitro model system for ABB and investigated the trafficking of ABB complexes using 4-D confocal fluorescence imaging of ABB complexes with transferrin or epidermal growth factor, well-characterized intracellular trafficking markers. Our data showed that cells expressing gE-gI and the viral antigen HSV-1 gD endocytosed anti-gD IgG and gD in a gE-gI-dependent process, resulting in lysosomal localization. These results suggest that gE-gI can mediate clearance of infected cell surfaces of anti-viral host IgG and viral antigens to evade IgG-mediated responses, representing a general mechanism for viral Fc receptors in immune evasion and viral pathogenesis.

SUBMITTER: Ndjamen B

PROVIDER: S-EPMC3946383 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface.

Ndjamen Blaise B Farley Alexander H AH Lee Terri T Fraser Scott E SE Bjorkman Pamela J PJ

PLoS pathogens 20140306 3

The Herpes Simplex Virus 1 (HSV-1) glycoprotein gE-gI is a transmembrane Fc receptor found on the surface of infected cells and virions that binds human immunoglobulin G (hIgG). gE-gI can also participate in antibody bipolar bridging (ABB), a process by which the antigen-binding fragments (Fabs) of the IgG bind a viral antigen while the Fc binds to gE-gI. IgG Fc binds gE-gI at basic, but not acidic, pH, suggesting that IgG bound at extracellular pH by cell surface gE-gI would dissociate and be d ...[more]

PMID: 24604090

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Project description:Like all the herpesviruses, herpes simplex virus encodes machinery that enables it to move through cell junctions to avoid neutralizing antibodies. This cell-to-cell spread mechanism requires the viral fusion machinery (gD, gH/gL, and gB) and numerous accessory proteins. Of all of these, minor alterations to only four proteins (gB, gK, UL20, or UL24) will dysregulate the fusion machinery, allowing the formation of syncytia. In contrast, removal of individual accessory proteins will block cell-to-cell spread, forcing the virus to transmit in a cell-free manner. In the context of a Syn variant, removal of a required accessory protein will block cell fusion, again forcing cell-free spread. This has been investigated most thoroughly for gBsyn variants, which lose their syncytial phenotype in the absence of several accessory proteins, including gE, gI, UL16, and UL21, which are known to physically interact. Recently it was found that UL21 is not needed for gKsyn-, UL20syn-, or UL24syn-induced cell fusion, and hence it was of interest to ascertain whether gE, gI, and UL16 are required for Syn variants other than gBsyn. Null mutants of these were each combined with seven syncytial variants distributed among gK, UL20, and UL24. Surprisingly, very different patterns of accessory protein requirements were revealed. Indeed, for the three gKsyn variants tested, two different patterns were found. Also, three mutants were able to replicate without causing cytopathic effects. These findings show that mutations that produce Syn variants dysregulate the cell-to-cell-spread machinery in unique ways and provide clues for elucidating how this virus moves between cells.IMPORTANCE Approximately 2/3 of adults worldwide are latently infected with herpes simplex virus 1. Upon reactivation, the virus has the ability to evade neutralizing antibodies by moving through cell junctions, but the mechanism of direct cell-to-cell spread is poorly understood. The machinery that assembles between cells includes the viral fusion proteins and various accessory proteins that prevent cells from fusing. Alterations in four proteins will dysregulate the machinery, allowing neighboring cells to fuse to make syncytia, but this can be prevented by removing various individual accessory proteins to further disable the machinery. Previously, the accessory protein UL21 was found to be important for the activity of some syncytial variants but not others. In this study, we discovered that UL16, gE, and gI all act differently in how they control the fusion machinery. A better understanding of the mechanism of cell-to-cell spread may enable the development of drugs that block it.

Dataset Information

The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface.

Publications

The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface.

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