PATHOGENESIS AND CHEMOTHERAPY OF HERPES VIRUS INFECTIONS IN MAN

点击翻译按钮获取中文摘要

The goals of this project are to characterize the pathogenesis, natural history and therapy of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Our clinical emphasis has been on oral and genital herpes and zoster in normal and immunocompromised hosts. Over the years we established the value, long term efficacy and safety of oral acyclovir for suppression of recurrent genital herpes and more recently oral herpes as well. We recently completed collaborative studies of sorivudine, a new drug for zoster. We seek evidence of persistent acyclovir-resistant HSV infections in immunologically normal individuals. Several studies are designed to uncover immunologic factors that correlate with more rapid and efficient resolution of herpetic outbreaks. This has involved analysis of HLA haplotypes associated with asymptomatic disease, as well as cytokine and cytotoxic T cell responses that predict milder disease. The major basic research goal has been to define molecular aspects of HSV and VZV latency and pathogenesis. We are examining the role of the HSV 1 and 2 latency- associated transcripts (LAT) in control of virus latency and reactivation. Recombinant viruses deleted for LAT expression and which contain targeted mutations in the LAT promoter are being studied in vitro and in animal models. We have begun to create transgenic mice expressing HSV genes neighboring and/or including the LAT gene. This past year we established mouse ocular and guinea pig genital models of acute and latent HSV1 and HSV2 infection so that the comparative pathogenesis of these infections can be studied. We succeeded in correlating disease severity and recurrence rates with levels of genome and its expression in neural tissues. Work on VZV latency and gene regulation has concentrated on genes 4, 10, 28, 21, 61, 62, and 63. Because gene 29 is expressed in latency and 28 is not, we are studying the regulation of these two genes. We found that they share a common and overlapping promoter, and are studying mechanisms by which VZV and nuclear regulating genes interact in affecting viral latency.