Regulation of the initial stages of herpes simplex virus lytic infection and reactivation from latency

Herpes simplex virus type 1 (HSV-1) is one of several herpesviruses that infect a high proportion of the human population. Although these viruses do not generally cause dangerous diseases, herpesvirus infections can become serious or even fatal in the newborn and those with damaged immune systems. Genital herpes simplex virus infections are one of the most common sexually transmitted diseases. Herpesviruses are common because after an initial infection they attain a latent state and are carried by the individual for life. As there are no treatments to eradicate latent virus, an understanding of how herpesviruses attain, maintain and reactivate from latency is necessary for improved treatments for herpesvirus diseases. Current research aims to elucidate the molecular mechanisms by which lytic and latent HSV-1 infection are regulated. HSV-1 encodes regulatory proteins that interact with cellular proteins and control systems, either interfering with or hijacking them to serve the needs of the virus. An understanding of these processes will reveal new possibilities for interfering with virus growth and reactivation from latency. Our results will contribute to improved understanding of processes that are important for normal and cancerous cells. The work is laboratory-based and involves biochemistry, molecular biology, microscopy and infection of cultured cells.

There are several herpesviruses that infect a high proportion of the human population. Although these viruses do not generally cause dangerous diseases, in certain groups of people, particularly the newborn and those with damaged immune systems, herpesvirus infections can become serious or even fatal. Herpesviruses are common because after an initial episode of infection, they attain a latent state so that they are carried by the infected individual for life. As there are no treatments to eradicate latent virus, an understanding of the molecular mechanisms by which herpesviruses attain, maintain and reactivate from latency is necessary for improved treatments for herpesvirus diseases. The balance between latent and lytic herpesvirus infections is governed by both viral and cellular factors, and by antiviral mechanisms that include not only the various arms of the immune defence but also mechanisms that operate via constitutively expressed proteins at the cellular level. This latter phenomenon, which is a relatively recent concept, is known as intrinsic immunity, intrinsic antiviral defence, or intrinsic resistance.

The principle aim of this programme is to decipher the mechanisms of action of herpes simplex virus type 1 (HSV-1) regulatory protein ICP0, which is required for efficient initiation of lytic infection and reactivation of latent virus. The main role of ICP0 is in counteracting intrinsic antiviral defence. We have shown that ICP0 is a ubiquitin E3 ligase that targets cellular intrinsic resistance proteins for destruction by the proteasome pathway. Current research aims to define the mechanisms of substrate targeting by ICP0 and to correlate these activities with the role of ICP0 in the regulation of viral infection. Our approaches utilise cultured cell systems of virus infection.
A major target of ICP0 is the cellular protein PML, a component of nuclear sub-structures known as PML Nuclear Bodies (PML NBs). PML and other PML NB proteins are rapidly recruited to sites associated with infecting HSV-1 genomes, a process that represents an intrinsic cellular response that represses viral gene expression. An important role of ICP0 is to inactivate this response to allow efficient infection. We have determined the molecular basis of the recruitment of PML to HSV-1 genomes and we have found that this mechanism underlies the recruitment of a number of other cellular proteins. We are extending these studies to the regulatory proteins of other herpesviruses, in particular human cytomegalovirus, to determine how their functions and mechanisms of action relate to those of ICP0. The results are expected to increase understanding of processes common to several DNA viral infections. Since components of PML NBs have been implicated in many important cellular control pathways, our experiments are likely to contribute to many aspects of cell biology research.