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. Over the past two decades we have studied antiviral drugs for the acute and suppressive management of genital herpes and severe HSV infections in immunocompromised subjects, and attempted to identify host immune factors that are associated with disease recurrence and severity.In the past few years, the major efforts have been in the laboratory. Our goal has been to elucidate 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 latent HSV-1 and -2 genome loads in human trigeminal and sacral ganglia harvested at autopsy and in experimentally infected animals. (2) Characterization of cytokine and other inflammatory contributors to HSV reactivation, through the provocation of reactivation and through the study of targeted knockout mice infected with HSV-1 or -2.As regards studies of HSV latency, we have refined mouse ocular models of HSV-1 and 2 infection. We can establish latency, quantitate virus load, latency gene expression, and induce reactivations with heat of ultraviolet heat. We used this model to study the relative potency of new antiviral drugs in preventing latency, and the role of several cytokines in establishment of latency and reactivates by infecting gene knockout mice. Specifically, we showed that IL-6, Fas, and IFN-gamma have no primary role to play in the establishment of latency or the reactivation of virus following UV irradiation. Loss of IL-6 or IFN-gamma, but not Fas, did lead to more severeprimary infections. In ongoing studies of latent viral DNA load in human ganglia, we found abundant HSV-1 NDA (average of 3x103 copies/105 ganglian cells) in most trigeminal ganglia, but little HSV-2 DNA (102 copies) in few ganglia. In contrast, we found abundant HSV-2but no HSV-1 NDA in some sacral ganglia. In our major initiative, we generated and studied mice transgenic for the HSV-2 genome region encoding the major latency associated transcripts (LATs). We prepared 6 founders, and bred two of them to homozygosity. We showed that the LATs are expressed abundantly in selected tissues, especially the sensory neurons. Transgenic expression of LAT had no effect on the course of acute HSV-2 infection, the establishment of latency nor the rate of reactivation following UV irradiation.
Showing the most recent 10 out of 12 publications
