This application proposes to examine the role of the HSV IgG Fc receptor (FcR) in immune evasion. HSV glycoproteins gE and gI form the FcR, which binds the Fc domain of human anti-HSV antibodies blocking Fc-mediated functions including complement activation and antibody-dependent cellular cytotoxicity. The goals are: (1) to construct and characterize gE and gI mutant viruses with mutations in the Fc binding regions. The mutants will be assessed for FcR activity, spread in cell culture, and transneuronal spread in a mouse eye model. (2) Mutants defective in FcR activity but intact for cell spread will be used to define the biological relevance of the HSV-1 FcR in vivo. The mutants will be tested for their ability to cause disease at the site of inoculation and via zosteriform spread in a mouse flank model. The importance of the FcR in viral pathogenesis will be assessed by passive transfer of either human or murine IgG to animals inoculated with FcR+ or FcR-viruses. The hypothesis to be tested is that human IgG will be more active against FcR- than FcR+ viruses because the IgG Fc-domain is available to activate complement and mediate ADCC. (3) The investigators propose to try and block HSV FcR-mediated immune evasion by immunizing with gE or gI. Candidate gE and gI immunogens include full length and secreted forms of gE and gI, and peptides or fusion proteins that target specific Fc binding domains. If antibodies to these immunogens block FcR activity, the immunogens will be added to a gD vaccine to determine if the combination improves efficacy. The investigators suggest these studies will address mechanisms of HSV immune evasion and may result in novel strategies for the development of subunit HSV vaccines.
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