Herpes simplex virus (HSV) glycoproteins gE and gI encode Fc receptors (FcR) that hind the Fc domain of immunoglobulin G (IgG). The HSV FcR protects the virus or infected cell from antibody attack. Studies to define the structure and function of the FcR are necessary if we are to understand mechanisms used by HSV to evade the host's immune response. our long term goal is to use this information to design better vaccines since it may not be possible for vaccine-induced antibodies to work effectively in clearing virus unless we prevent the activity of the FcR.
Our specific aims are to define domains on gE-l and gI-l involved in Fc binding; to examine the role of the FcR in pathogenesis; and to compare the FcR activity of HSV-1 and HSV-2. To define binding domains, we will mutate the gE-l and gI-l genes, clone the mutant genes into expression plasmids, transfect cells, and study IgG binding to the glycoproteins. To examine the role of the FcR in pathogenesis, we will clone the mutant genes back into virus to replace wild type gE-l or gI-l. Pathogenesis studies will address the importance of antibody bipolar bridging in immune evasion. Bipolar bridging refers to the binding of an antibody molecule by its Fab end to viral antigen and by its Fc end to the HSV FcR. We will examine whether bipolar bridging blocks effector functions mediated by the Fc fragment of IgG, such as Clq binding, complement activation, and attachment of IgG to FcRs on host immune cells. We will compare virulence of wild type and FcR mutant viruses in mice, using the footpad route of inoculation. We will observe mice for progression of disease and establishment of latent infection within ganglia. The mouse model is useful because murine IgG does not bind to the HSV FcR. This permits us to control conditions under which the HSV FcR participates in pathogenesis. We will passively immunize mice with antibodies from rabbits, since rabbit IgG binds to the HSV FcR. Our hypothesis is that viruses with intact FcRs will be protected from the antiviral effects of rabbit IgG. Finally, we will compare FcRs of HSV-1 and HSV-2 to determine whether their FcRs function similarly to modify host immune attack.
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