BIOLOGY OF MAMMALIAN HOMEODOMAIN PROTEINS

单纯疱疹病毒是一种重要的人类相关病原体

Herpes simplex virus is an important human pathogen associated with diseases ranging from mild recurrent genital or facial lesions to fatal infections of newborns. It has been postulated that in vivo, the regulation of the immediate early (IE) genes of HSV-1 may control the severity of an infection and whether the infection will by lytic or remain latent, In order to define intracellular host and viral factors that might control IE gene expression in vivo, we have focused on proteins capable of interacting with the TAATGARAT regulatory regions of IE genes. We have found earlier that in vitro, the mouse homeodomain protein Hox 1.3 binds TAATGARAT motifs. To test whether overexpression of Hox 1.3 would alter HSV-1 pathogenesis, we generated transgenic mice in which the level of Hox 1.3 is regulated by virus infection (by way of responding to a virus/interferon-inducible promoter). Such transgenic mice are indeed markedly more susceptible to lytic HSV-1 infection, most likely because Hox 1.3 protein is induced in the very cells that become infected upon exposure to HSV-1. To study whether this increased susceptibility to HSV-1 is due to a direct action of Hox 1.3 on the IE gene regulatory region, we have generated additional transgenic mice that express the bacterial beta-galactosidase reporter gene under an IE gene promoter and we crossed these mice with the Hox 1.3 transgenics. In double transgenic mice, we will induce the Hox 1.3 protein with interferon and test whether this induction would result in transactivation of the reporter gene. In addition, we have generated transgenic mice that harbor a cDNA for a truncated form of the viral VP16 protein that is incapable to transactivate IE genes but capable to compete with wild type VP16. These lines of mice have been expanded on a HSV-1 susceptible background and will become ready to test for alterations in the course of HSV-1 infection and latency in the near future. This project will be continued by Dr. Mitchell in LNEP.