ROLE OF CHROMATIN IN HERPES SIMPLEX VIRUS TYPE 1 (HSV-1) GENE REGULATION

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our laboratory studies the molecular and cellular biology of HSV-1 during lytic and latent infections including the mechanisms of gene silencing and reactivation. We investigated the roles of TR and T3 on HSV-1 gene expression in vitro after identifying the thyroid hormone receptor (TR) responsive elements (TREs) in the promoters of HSV-1 TK and LAT. We demonstrated that liganded TR repressed TK promoter activity by transfection and infection of neuronal cells. Our data also showed that the liganded TRs activated LAT transcription but repressed ICP0 transcription. TRs were recruited to these promoters independently of T3 and hyperacetylated histones H4 was associated with these promoters in the presence of hormone. In addition, various chromatin modifying complexes such as CTCF and BRG1 complexes were recruited to these promoters in the presence of TR and T3. Furthermore, T3-treated N2aTR¿ cells were suppressive to TK expression and virus egress at low moi but the abstraction of hormone enhanced the TK expression and thus increased the release of infectious viruses. These results, for the first time, suggested that T3 could regulate the HSV-1 infections and may have a role in viral latency and reactivation in vivo. Studies using animal models are underway. We also investigate a candidate antiviral drugs that we have developed in collaboration with Dr. El Sayed. The results showed that an alkaloid Manzamine A exhibits significant inhibitory effect on viral infection in a corneal cell line at 1¿M. These results suggest that it may have great potential to prevent HSV-1 induced eye infection.