A long standing goal of this Section has been the development of new therapeutic and preventative strategies for human herpesvirus infections and better definition of their pathogenesis. Notable past achievements have included the development of acyclovir as a suppressive treatment for recurrent oral and genial herpes and identification of drug resistant strains in immunocompetent patients. We recently completed two studies aimed at determining why some people develop frequently symptomatic herpes outbreaks while others do not. We undertook one protocol to compare HLA haplotypes in 3 sets of subjects: individuals who are seronegative for both HSV1 and 2, individuals who are seropositive for HSV2 but fail to recognize recurrent outbreaks, and individuals who are HSV2-positive and have frequent clinical outbreaks. We have identified statistically significant haplotypes that distinguish patients with frequent recurrences from uninfected individuals and individuals with no symptoms and which distinguish infected form uninfected persons. In another clinical research protocol we recover lymphocytes from patients before, during, and between episodes of recurring genital herpes and we are studying the release of specific cytokines from their lymphocytes in vitro in response to HSV antigens. We have studied the release thus far of approximately 12 cytokines and have preliminary clues to differences in cytokine patterns between recurrences. The differences are not substantive, so as to explain the clinical differences among these individuals. A second major goal of this section is the elucidation of pivotal molecular and cellular events which define and contribute to the pathogenesis of acute , chronic, and recurring infections with human herpesviruses. Major current projects fall into two areas: (1) Analysis of infection and gene expression by varicella-zoster virus; and (2) Comparative biology and molecular analysis of latent infections of animals and humans with herpes simplex virus types-1 and 2. As regards to studies of VZV infection we have identified specific genes that are expressed during virus latency in human cells. We have begun a new project recently in which we are studying the regulation, transcription, expression, and persistence of VZV gene 21, whose product appears to be expressed during latency in infected rats and humans. To date, we completed detailed mapping of the VZV gene 21 transcript and the responsiveness of its promoter to VZV transregulatory genes. In 2 separate studies we are examining latent VZV gene load and expression. We developed a novel model of latent VZV infection by intraperitoreal injection of neonatal rats. Preliminary data using PCR show latent genome in most animal trigeminal ganglia at 4-6 weeks post-infection, and presence of gene 21 but not gene 40 message, in accord with data from human studies. In other studies, we cloned and expressed VZV envelope glycoproteins in baculovirus. We proved these proteins to be immunogenic and to partially protect guinea pigs from VZV- induced chronic uveitis. As regards studies of HSV latency, we have refined mouse ocular models of HSV-1 and 2 infection. We can establish latency, quatitate virus load, latency gene expression, and induce reactivations with heat of ultraviolet heat. We are using this model to study the relative potency of new antiviral drugs in preventing latency, and we are studying the role of several cytokines in establishment of latency and reactivates by infecting gene knockout mice.
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