PATHOGENESIS AND CHEMOTHERAPY OF HERPES VIRUS INFECTIONS IN MAN

这个项目的目标是描述发病机制，自然的 单纯疱疹病毒和水痘-带状疱疹的历史和治疗 病毒(VZV)感染我们的临床重点一直放在口腔和 正常和免疫受损宿主的生殖器疱疹和带状疱疹。完毕 多年来，我们确定了口服的价值、长期疗效和安全性 阿昔洛韦治疗复发性生殖器疱疹 口腔疱疹也是。我们最近完成了关于 治疗带状疱疹的新药索里夫定。我们在寻找证据证明 免疫正常人群中的阿昔洛韦耐药单纯疱疹病毒感染。 有几项研究旨在揭示免疫因素 与更快、更有效地解决疱疹暴发有关。 这涉及到分析与无症状相关的人类白细胞抗原单倍型。 疾病，以及细胞因子和细胞毒性T细胞反应，预测 病情较轻。 主要的基础研究目标是确定单纯疱疹病毒的分子方面 以及VZV潜伏期和发病机制。我们正在研究HSV的作用 控制病毒潜伏期的1和2潜伏期相关转录本(LAT) 和重新激活。为LAT表达而删除的重组病毒和 在LAT启动子中含有靶向突变的基因正在研究中 在体外和动物模型中。我们已经开始创造转基因小鼠 表达与LAT基因相邻和/或包括LAT基因的HSV基因。这 在过去的一年里，我们建立了小鼠眼部和豚鼠生殖器模型。 急性和潜伏性HSV1和HSV2感染的比较 这些感染的发病机制可以研究。我们成功地 疾病严重程度和复发率与基因组水平的关系 以及它在神经组织中的表达。 对VZV潜伏期和基因调控的研究主要集中在基因4，10， 28、21、61、62和63。因为基因29在潜伏期和28中表达 不是，我们正在研究这两个基因的调控。我们发现 它们共享一个共同和重叠的启动子，并正在研究机制 VZV和核调控基因通过什么相互作用影响病毒 延迟。

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.