Reactivated HSV-1 disease in immune compromised hosts

说明：（由申请人提供）疱疹病毒感染是非常严重的

DESCRIPTION: (Provided by the Applicant) Herpes virus infection is a very common recurrent health problem in humans, especially immuno suppressed individuals. After resolution of primary infection, a state of latency develops that persists until death. Environmental stimuli such as UV lead to periodic recrudescence of disease. The investigators have recently developed a powerful murine model of reactivated HSV disease of epithelium that is stimulated by a minimum UV exposure. This very closely mimics HSV epithelium disease in man, permitting study of cutaneous HSV-1 reactivation in a relevant experimental system. The studies proposed in this application will use this model to test the hypothesis that reactivated HSV-1 disease is due to a disruption in local cytokine balance, and disease resolution requires local cutaneous immunologic changes. They propose to study the immunopathology of HSV disease reactivation and suggest new treatments and vaccine strategies. They hypothesize that UV exposure results in secretion of soluble factors by keratinocytes that ultimately alter the TH1/TH2 balance which induces HSV from reactivation. Lack of CD4 responses in CD4 depleted animals then permit severe and prolonged disease. They propose that modulation of local immune factors including IL-12 and IFN-gamma alter the reactivation process and that differences of components of the local immune systems impact susceptibility to HSV-1 infection. Studies will be done in immune competent mice and in mice depleted of CD4 which yields reactivated HSV disease in a manner very similar to human HSV disease in HIV infected hosts. Specifically, they will characterize the immune response to HSV-1 at the local cutaneous level and to define the context of interplay of cytokines and immune cells during reactivated cutaneous HSV-1 disease; determine the role of infiltrating T lymphocytes in primary and reactivated disease in normal versus immune compromised models; and determine efficacy of genomic vaccine candidates in prevention of primary infection and in attenuation of reactivated disease.