The prevalence of genital herpes simplex virus (HSV) infection continues to increase. HSV is incurable and causes significant morbidity and mortality. The general mucosa is an important site of HSV infection. Little is currently known concerning the virologic correlates, maintenance, phenotype, or antigenic specificity of the mucosal cellular immune response to HSV. The correlation of local CTL with viral clearance from cutaneous genital HSV-2 lesions has lead to the hypothesis that mucosal CTL are important in the control of cervical HSV-2 infection. To investigate this hypothesis, techniques have been developed to recover and culture cervical lymphocytes and measure HSV-specific CD4 and CD8 cytotoxic lymphocytes. Objective measures of the rates of subclinical, clinical HSV, and total virus shedding in women demonstrate up to 10-fold differences in total virus shedding among immunocompetent women. The initial Specific Aim is to investigate the relationship between the rate of shedding of HSV-2 in women with genital herpes and each of several parameters of the local and systemic lymphocyte response to HSV. The second Specific Aim will investigate the requirement for local presentation of viral antigen for maintenance of local mucosal cellular and humor immune responses to HSV, by sampling women before, during, and after suppression of viral replication with daily antiviral medication. Since vaccination strategies differ in their elicitation of antigen- specific CD4 and CD8 responses, the third Specific Aim is to determine the phenotype of cervical CTL in HSV-2 infected women. As vaccines based on HSV envelop glycoproteins have failed, the final Specific Aim will apply an expression cloning, successful in defining novel HSV-2 GT cell antigens recognized by skin-infiltrating CD4 T-cells, to cervical CD4 and CD8 HSV- specific T-cells. These studies will evaluate immune correlates of the virologically defined spectrum of HSV disease severity and assist with the prioritization of strategies and antigens for possible use in immunologically based therapies for HSV.
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