Differential targeting of the HSV1 vhs endoribonuclease - preferential degradation of cellular transcripts on the endoplasmic reticulum?

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Herpes simplex virus (HSV) is an important human pathogen of medical and economic impact. HSV infection is life-long and once acquired it remains dormant in the body, poised to re-emerge and cause disease. It is the causative agent of recurring oral and genital herpes, both of which have profound effects on the quality of life of sufferers. Upon activation, HSV can also have much more serious consequences. For example, it is a pioneer infection for human immunodeficiency virus (HIV), making individuals more susceptible to HIV infection. It is the major cause of infectious blindness, and viral encephalitis that results in death or devastating brain damage. In developing countries neonatal herpes remains a cause of death in newborns. Individuals who have a suppressed immune system, such as transplant, cancer chemotherapy, and AIDS patients, are particularly susceptible to complications of HSV. With 24 million new cases globally each year, this virus is a huge economic burden on our health systems. However, efforts to develop an HSV vaccine have, without exception, failed. Moreover, although drug treatments for HSV have existed for decades, their use has made no impact on this HSV epidemic and resistance is growing. It is therefore vital that new ways to treat HSV are identified.To understand how to treat virus infections, it is first important to understand how they cause disease. HSV produces a number of factors that are considered non-essential for infection in cells in the lab, but are vital for the virus to cause disease in the host animal. These factors represent new targets for therapuetic intervention. One of these is virion host shutoff (vhs), which has a role in controlling the global cellular environment to make it favourable for efficient virus growth. Nonetheless, it is not yet clear how vhs activity influences the outcome of the disease process in a balanced fashion, such that it does not create a hostile environment for the virus. Using a global approach to look at cellular changes in HSV1 infection, we have discovered that vhs appears to target specific groups of cellular factors involved in pathways that determine the make-up of the environment outside the cell. Here, we propose to use state-of-the-art technology to define in detail the targets that are highly susceptible to vhs activity. New tools will be developed to identify the infected cell components that interact with vhs to understand how vhs is targeted to its site of action. Finally, we will determine if the activity of vhs prepares the cell to make large numbers of virus structual components thereby enabling the efficient production of new virus particles. In this way we aim to unravel the complexities of vhs activity to further our understanding of its role in virus infection and identify target interactions to potentially inhibit therapeutically.