MECHNISM OF HERPES ST ROMAL KERATITIS

City Of Hope/Beckman Research Institute, Duarte CA

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Abstract

Herpes stromal keratitis (HSK), a leading cause of infectious blindness in the western world, is an inflammatory disease that results from herpes simplex virus type 1 (HSV) infection of the human eye. Recent results suggest that HSK is an autoimmune disease triggered by HSV infection, through a mechanism involving molecular mimicry whereby ocular-antigen reactive T cells are activated by cross recognition of an HSV-1 capsid antigen. However, other studies have shown that while viral replication is required for clinical HSK, recognition of HSV antigens by CD4+ T cells may not obligatory. Rather, it appears that HSV infection serves to provoke the proinflammatory environment responsible for recruitment and activation of effector CD4+ T cells in the cornea. The observation that pathogenic CD4+ T cells infiltrate the cornea at a time when neither infectious HSV nor viral antigen can be detected in the cornea raises questions about the precise role of HSV replication in this process. However, an important observation is that HSV DNA persists in the cornea for months and is found localized to sites of inflammatory lesions by in situ-PCR. Intriguingly, there is a correlation between persistence of HSV DNA and the propensity of different HSV strains to induce HSK; thus DNA from HSV RE, a strong inducer of HSK compared to KOS persists, while HSV KOS DNA does not. We propose testing the hypothesize that HSV DNA persisting in the cornea can induce the proinflammatory environment that drives activation of CD4+ T cells, perhaps of indiscriminant specificity, into effectors mediating HSK. In support of this hypothesis are our results demonstrating that HSV DNA contains potent immunostimulatory CpG motifs (CpG) that can both activate spleen cell proliferation and cytokine synthesis in vitro, and act as a potent adjuvant priming Th1-type CD4+ and CD8+ T cell responses to a protein antigen (ovalbumin) in vivo. We recently observed that gender strongly influenced the outcome of HSV infection including the severity of HSV eye disease and showed that in part, this could be due to the effects of sex hormones on the immune response to HSV. Given that sex hormones are known to affect antigen presentation we propose examining their effects on inflammatory responses mediated by HSV-1 DNA in vitro and the incidence and/or severity of HSK in vivo.