Role of the Human Cytomegalovirus Major Immediate-Early 1 Protein in Viral Reactivation from Latency

Human cytomegalovirus or hCMV is one of eight herpesviruses that are known to infect people. This virus is very common, infecting one out of two persons in the UK. Once hCMV is in a person's body it stays there for life, usually in a dormant state referred to as "latency". In latency, few viral genes are active and no virus is produced. Although hCMV likely remains latent in several places of the human body, blood and bone marrow cells of the "myeloid" type are the best known sites of hCMV latency. Most healthy adults and children who become infected will have few signs or symptoms and no long-term effects from hCMV. However, people at risk include those with weakened immune systems including individuals who receive transplants, undergo cancer chemotherapy or are positive for HIV. It is well established that in these people, hCMV can cause life-threatening disease affecting multiple organs. However, the fact that hCMV is also the leading cause of congenital (present at birth) infections worldwide is less appreciated, and so is the socioeconomic impact of this virus as the most common cause of childhood hearing loss and brain disorders. Two to three babies are damaged by hCMV every day (almost 1,000 babies every year) in the UK. In fact, hCMV causes more birth defects and childhood deaths than Down's syndrome, toxoplasmosis or listeriosis and is a greater global health concern than the Zika virus. Yet, congenital hCMV lacks awareness among health care workers and the public. Furthermore, no vaccine for this virus is available and no approved treatment for congenital infection exists, since all available drugs have dangerous side effects. Consequently, there is an urgent need to identify new molecular targets and better drugs for hCMV. Although hCMV may cause serious symptoms upon initial infection of people at risk, disease more typically ensues when the virus "reactivates" in latently infected individuals. Reactivation from latency is considered to be a stepwise process that ultimately results in the global activation of viral genes and production of infectious virus. How hCMV reactivates from latency is far from clear, especially at the molecular level. Much of our previous research has centred on an hCMV protein known as immediate-early 1 or IE1. IE1 is believed to be the very first viral protein produced during hCMV reactivation and is therefore expected to have an important role in this process. Based on preliminary experiments, we propose that IE1 serves as a key viral factor in hCMV reactivation via at least two molecular mechanisms involving host proteins of the signal transducer and activator of transcription (STAT) family and nucleosomes, the basic building blocks of chromatin, respectively. We will employ state-of-the-art technology using infected human myeloid cells as a model to elucidate how exactly IE1 modulates molecular pathways linked to STAT proteins to reactivate virus production. Likewise, we will identify chromatin-based "epigenetic" mechanisms underlying IE1-mediated reactivation of viral genes. Finally, we will evaluate agents targeting the molecular events linked to IE1-mediated reactivation for their antiviral capacity and potential to serve as candidates for drug development. The results from this work will considerably improve our limited molecular understanding of how hCMV reactivates from latency to cause disease. They will also reveal new strategies to combat this important, but somewhat neglected, human pathogen.