Grant: Discovery Grants Program - Individual

Infection with a herpesvirus (the human herpes simplex virus, HSV-1 is an example) begins with active replication of the virus in skin cells at the site of entry. The virus then infects sensory nerves innervating the area of virus replication and establishes a latent infection in nerve cells. Here it quietly remains, protected from the host's defenses. In response to environmental or physiological stress the latent virus in nerve cells reactivates periodically to replicate and reinfect skin cells. The molecular basis for the establishment of latency has long been an intriguing and perplexing puzzle for virologists, a puzzle that has not as yet been solved. The objective of our research is to determine how HSV-1 senses when its host is stressed. Our work will not only help us to understand how herpesviruses establish latency and reactivate from it, it will also tell us how cells of the nervous system respond to stress. ) We have discovered two human proteins, which may hold the key to herpesvirus latency and reactivation. We have named these proteins Luman and Zhangfei after mythical characters in the Beijing opera. In pain-sensing nerve cells (the very cells in which HSV becomes latent) in unstressed animals Zhangfei appears to suppress HSV-1 replication and, we think, directs it into latency. Luman is capable of activating HSV-1 gene expression and we think that in the nerve cells of stressed animals it reactivates latent virus. ) During our studies we have discovered some interesting things about what Zhangfei's normal role in the animal might be. It seems to be involved in the development of the pain-sensing nerve cells in the developing embryo. In medulloblastoma (a childhood nerve cell cancer) no Zhangfei is made. However, if we now get these rapidly dividing cells to make Zhangfei, they stop dividing and start looking like mature nerve cells. ) Over the next five years we propose to investigate how Zhangfei and Luman influence HSV-1 replication, latency and reactivation. We will also try to find out what the two proteins do in normal, uninfected nerve cells.