Herpes simplex virus 2 (HSV-2) is a common, sexually acquired virus that causes recurrent genital sores and can be transmitted to children of infected mothers during birth. Design of a vaccine strain that protects against HSV, and an understanding of the mechanisms of immune interference in HSV pathogenesis are primary goals of our research. We have utilized virus strains containing engineered mutations in genes essential for virus replication as a vaccine prototype. These viruses express numerous proteins in infected cells but do not reproduce and spread. Mice immunized with replication-defective mutants of HSV-2 develop a long-lived immune response that protects them against disease upon genital infection with virulent HSV-2. We are determining the role of different immune effectors in mediating protection against sexually transmitted disease, and the importance of T cell costimulation activity in induction of antiviral immunity. In addition, we are using molecular genetics to improve the immunogenicity of replication-defective viruses, inserting immune modulatory molecules into the virus' genome and abrogating viral immune evasion strategies.
A collection of viral proteins between the virion envelope and capsid comprises the HSV tegument. Its constituents perform essential functions that regulate viral and host cell process during infection. The virion host shutoff (vhs) tegument protein rapidly degrades host mRNA to assert control over host macromolecular synthesis. HSV-2 mutants defective in vhs activity are highly attenuated in vivo. We found that virulence is restored by infection of mice incapable of responding to type I IFN, implicating vhs in blockade of the host type I IFN response. We are investigating the mechanism of vhs interference with this innate response to virus infection. A third area of research is phosphorylation of tegument components mediated by the UL13 viral kinase, and the synthesis, modification and function of the VP22 protein, one of the targets of UL13 activity. We have extensively mutated phosphorylation sites on VP22 and will incorporate this hypophosphorylated form of VP22 into the virus to assess function of UL13-mediated phosphorylation in vitro and in vivo.