Herpes Simplex Virus Pathogenesis
Herpes viruses, and especially herpes simplex virus (HSV), are among the most successful human pathogens. Herpes viruses have evolved diverse strategies to evade the host immune response, which is the major factor accounting for their success. Their ability to establish a lifelong latent infection is a particularly effective immune escape mechanism, since the virus can reactivate later giving rise to recurrent disease and a source of virus that can be transmitted to susceptible individuals.

We are studying HSV pathogenesis with the long-term goal of understanding latency at a molecular level. This knowledge will facilitate rational approaches for control of recurrent HSV infections and perhaps ultimately to a "cure." Current projects in the laboratory are focused on determining a role for cytokines in the control of acute and reactivated HSV infections. Using cytokine ligand and receptor knockout mice, we showed that the IFN-γ receptor rather than IFN-γ itself was required for protection against HSV and Vaccinia virus infection. We interpreted this result as evidence for the existence of a novel ligand for the IFN-γR that mediates protection against viral challenge. In contrast, using an in vivo reactivation model, we demonstrated that IFN-γ was required for the control of reactivated HSV, though it was not involved in the maintenance of latency.

In an extension of these studies, we demonstrated that TNF mediates protection against HSV mortality independent of signaling through either of the two known TNF receptors, p55 and p75. Future studies will investigate whether protection mediated by TNF involves signaling through a novel TNF receptor. In the course of these studies, we discovered the existence of a novel locus adjacent to the p55 locus on murine chromosome 6 that dominantly determines resistance to HSV mortality and influences reactivation. We have named the locus Herpes resistance locus (Hrl ). A major focus in the laboratory now is high resolution mapping of Hrl with the goal of isolating the gene. Our strategy relies heavily on a bioinformatics approach exploiting the mouse and human genome sequences that are available to us through collaboration with a biotechnology research group. Cloning and characterization of Hrl will enable isolation of the human ortholog and enhance our understanding of innate resistance to viral infections and factors that control reactivation.

Two new research programs have also been initiated. The first concerns gender influences on the immune response to HSV infection, with particular emphasis on the role of sex hormones. During studies with the IFN-γ KO mice, we discovered strong sex-based influences on the outcome of infection with males being significantly more susceptible than females to HSV. A particularly interesting gender effect is that the null mutations in RGKO and GKO mice affect the susceptibility of male but not female mice to HSV, indicating that some effects of IFN-γ are gender-specific. Another new area of research is concerned with the intrinsic immunostimulatory activity of highly purified HSV DNA and oligos derived therefrom. We recently demonstrated that this immunostimulatory activity derives from the presence of non-methylated immunostimulatory CpG motifs in the HSV genome, similar to those present in bacterial DNAs, which are highly immunostimulatory. The goal of the project is to determine whether HSV DNA persisting in an inappropriate context, such as in abortively infected cells, might stimulate potentially damaging Th1 proinflammatory responses in the nervous system and eye, and thus contribute to pathogenesis.