THE ROLE OF GK IN HSV-1 INDUCED CORNEAL SCARRING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Herpes simplex virus (HSV) infections are among the most frequent serious viral eye infections in the U.S. and are a major cause of viral induced blindness. Ocular infection with HSV-1 can cause eye disease ranging from mild infection to loss of vision due to damage done to the cornea which is called corneal scarring. HSV-1 induced corneal scarring can lead to blindness and as such, HSV-1 is the leading cause of corneal blindness by an infectious agent in developed countries. It is estimated that 70-90% of the adult population in the U.S. have antibodies to HSV-1 and/or HSV-2, with about 25% showing clinical symptoms. It is estimated that there are 400,000 to 500,000 doctor visits annually in the United States for recurrent ocular HSV. Periodic ocular recurrences produces permanent visual disability by corneal scarring. Although the specific immune response leading to corneal scarring remains an area of controversy, it is well established that HSV-1 induced corneal scarring, and hence subsequent HSV-1 induced corneal blindness, is due to an immune response to the virus. The HSV-1 protein(s) against which this harmful immune response is directed is not known. Blood collection in limited to one blood draw per pateint. This research only evaluate blood collected from patients rather than a therapeutic or diagnostic intervention. Our animal studies suggest that in mice there is a strong correlation between severity of the eye disease and presence of antibody to one of HSV-1 protein call glycoprotein K (gK). In a small pilot study we have shown that sera from 3 humans with clinical HSV recurrences had high anti-gK antibody, while sera from 4 individula with no history of HSV-1 recurrences had no detectable anti-gK antibody. We want to confirm with a larger number of sera that individuals with ongoing recurrent disease have higher anti-gK antibody titers than asymptomatic individuals and test the hypotheses that anti-gK antibody correlates with recurrent clinical disease. Since both HSV-1 and HSV-2 infect the eye we now plan to confirm our preliminary studies in sera from HSV-2 infected individual. Therefore, we have established a collaboration with Dr. Anna Wald of University of Washington to test our hypothesis. Dr. Anna Wald had agreed to send us a total of 50 sera from HSV-2 infected individuals with and without history of HSV-2 infection. Dr. Anna Wald will collect the samples and ship the samples to CSMC. The specimens will have identifiers that only known to Dr. Wald and we will not have any access to a linking list at University of Washington. IN THE SECOND PART OF THIS STUDY WE ARE GOING TO LOOK AT THE INTERACTION OF INTERLEUKINE-2 (IL-2) AND HSV-1 in MS AND OPTIC NEURITIS AS DESCRIBED BELOW: Multiple sclerosis (MS) is a life-log chronic disease diagnosed primarily in young adults. It is estimated that 300,000 to 400,000 people have MS, with approximately 200 new cases being diagnosed weekly. Clinical symptoms of MS range from relatively benign to devastating as communication between the brain and other parts of the body is disrupted. While the cause and pathogenesis of MS is unknown, the working hypothesis is that autoimmunity to antigens of the CNS is triggered by environmental factors such as viral destruction. In our preliminary results, we have found that ocular challenge of mice with a recombinant herpes simplex virus type 1 (HSV-1) virus expressing murine interleukine-2 (IL-2) resulted in demyelination, as determined by histological examination at autopsy. The demyelination had striking similarities to that seen in MS. As with MS, the demyelination was focal and was found in ventral lateral white matter tracts in mid-brain to hind-brain areas. In addition, the mice developed transient complete (25%) or partial (75%) hind limb paralysis. In contrast, neither wild-type (wt) HSV infection alone nor HSV-IL-4, nor HSV-IFN-g virus (identical to HSV-IL-2 but expressing IL-4 or IFN-g instead of IL-2) infection caused demyelination. Our Preliminary Studies also suggest that IL-2 alone does not cause demyelination. Thus, in our model, when the virus or cytokine is administered individually disease does not occur; however, when administered together these agents cause demyelination and clinical abnormalities similar to those often observed in MS. In contrast to this proposal, the numerous animal models for MS that have been developed, generally use either the viral model or the direct autoimmune model to initiate disease. This proposal outlines the use of a novel model for demyelination that incorporates both a viral and an immune component. We now plan to test our animal findings in individuals with MS using peripheral blood Our overall working hypothesis is that, the combination of viral infection in the CNS and presence of IL-2 results in recruitment of CD8+ T cell and macrophages into the CNS. Following activation, the myelin-specific autoreactive CD8+ T cell directly cause demyelination, with the macrophages enhancing the demyelination by cross-presenting myelin fragments to CD8+ T cell as well as pushing the immune response toward a TH1 response. The goal of this study is to isolate the T cells from peripheral blood of individuals with MS during various period of relapsing- remitting and test the working hypothesis, thereby identifying molecules that may be effectively targeted for the prevention of the development or the exacerbation of MS.