Mechanisms of the humoral immune response to herpes simplex virus infection

Infection with herpes simplex virus (HSV) elicits innate and adaptive host immune responses. While clearance of peripheral viral infection is mediated by T lymphocytes, the humoral (antibody) response to HSV limits viral spread into the central nervous system and reduces the potential for life-threatening disease. In this thesis, we have addressed three aspects of the humoral response to HSV using mouse models. First, we have investigated the role of the complement system on the generation of the IgG antibody responses following infection with wild type HSV-1 strain KOS1.1. Using mice deficient for complement proteins C3 or C4 or complement C3 receptors Cr1 and Cr2, we observed that disruption of any of these proteins resulted in impaired generation of IgG antibody following intradermal HSV infection. We concluded that the humoral response to peripheral HSV infection is complement-dependent. Second, we assessed the impact of preexisting immunity on the efficacy of replication-defective HSV-1 and HSV-2-derived vaccine vectors. Using HSV-derived vectors expressing the model antigen β-galactosidase (β-gal), we investigated the ability of these vectors to generate β-gal-specific IgG antibody responses in mice pre-immunized with HSV. We observed that preexisting host immunity did not diminish the efficacy of HSV-derived vectors, because the generation of IgG antibody and the durability of the IgG response in mice was not affected by prior immunization. Finally, we investigated the mechanism of the durable immune response elicited by replication-defective HSV recombinants by evaluating the IgG antibody response following infection with replication-defective HSV-2 mutants. We observed that the IgG response to these mutants is durable, with ELISA titers that remained stable for at least one-year. In addition, we characterized the viral antigen specificity of the IgG response over time using Western blot analysis. We observed that the IgG response following replication-defective HSV infection is not static. In particular, a class of IgG developed or was significantly enhanced at late times post-infection. We proposed that this late/enhanced response may indicate antigen persistence following infection and may provide a mechanism for the ability of replication-defective HSV mutants to generate durable host immunity.