IMMUNOBIOLOGY OF GENITAL HSV-2 INFECTION IN GUINEA PIGS

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Acute and recurrent genital herpes remains a major health concern. In this application we propose to investigate the immune response to a number of HSV-2 polypeptides. We will then correlate these responses to the natural history of genital HSV-2 disease. We will also induce immunity to selected HSV-2 proteins prior to intravaginal challenge to examine the subsequent alterations in the natural history of the disease and also to boost selected responses after latency has been established to determine the consequences on recurrent HSV-2 infection. We have chosen to perform these evaluations using the guinea pig model of genital herpes because intravaginal HSV-2 inoculation of guinea pigs produces a self-limited genital disease and a latent infection in neural tissues. Unlike other small animal models, guinea pigs, however, also develop spontaneous clinically apparent recurrences that can also be induced by UV exposure. This unique model in inbred and outbred animals can, therefore, be used to evaluate the effects of immune intervention on virological and clinical manifestations of acute, recurrent and latent HSV-2 infections. We will develop vaccinia recombinants expressing selected HSV-2 polypeptides in order to induce immune responses to the selected HSV-2 polypeptides. We have chosen vaccinia because it has a wide host range and can incorporate large fragments of foreign DNA which are correctly processed in host cells. Further, inoculation with vaccinia can induce antibody and cell mediated immune functions, including cytotoxic T lymphocytes, to the foreign gene product. The polypeptides we will evaluate were selected because preliminary evidence with herpes viruses as well as other viruses suggests that these may be important antigens for antibody and especially cell mediated immunity. They include immediate early HSV-2 proteins, internal structural proteins, nonstructural proteins and glycoprotein C. The vaccinia recombinants developed as part of this application will also be used to make antigen and targets for antibody mediated immunity including immunoblot, ELISA and antibody dependent cellular cytotoxicity (ADCC) and cell mediated immunity including proliferation, and IL-2 as well as HSV specific MHC unrestricted (NK) and MHC restricted (CTL) assays. The overall goal of this proposal is to expand our understanding of the immune response to selected HSV polypeptides and their effects on acute and recur- rent genital herpes. This knowledge should ultimately provide new approaches to the control of this common public health problem.