Herpes simplex virus (HSV) continues to be the infectious agent responsible for most corneal blindness in the United States. Following the initial episode of HSV keratitis in man, there is approximately a 25% chance of recurrence within two years. Although antiviral drugs generally reduce the severity and duration of epithelial keratitis, existing drugs have not decreased the incidence of recurrence in the eye. The long-term objective of the proposed studies is to elucidate the mechanisms involved in he progression of acute HSV keratitis into latency and the eventual reactivation of latent virus responsible for recurrent ocular disease. We ultimately hope to identify ways to control and eradicate herpes infections. A recently developed mouse model of HSV recurrence will be further improved and then utilized to test the antiviral activity of several new compounds, such as FMAU, FIAC, and BIOLF-62. Anti-VP175, a marker for latency in infected cells, will be used in immunofluorescence procedures to monitor for VP175, an immediate early HSV polypeptide. Monoclonal antibodies to VP175 and other viral proteins have been and will continue to be developed. Improved methods for culturing trigeminal ganglia neurons, the reservoir for HSV, will permit us to enhance our detection of latent HSV. Viral activities in these neurons will be examined using 14C-FMAU and anti-VP175. In vitro drug studies will also be carried out on cultured latently infected neurons. Molecular probes (14C-FMAU and anti-VP175) will provide research data on DNA and virus protein synthesis during the latent and recurrent stages. FMAU is a potent new antiviral agent that is selectively phosphorylated by the viral thymidine kinase in HSV-infected cells; thus, radioactive labelled FMAU (14C-FMAU) provides a unique opportunity for studying viral DNA synthesis by autoradiographic techniques.
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