Human cytomegalovirus: changes in the latently infected cell as chemotherapeutic and immunological targets for antiviral therapy

Human cytomegalovirus (HCMV) is a type of herpesvirus which is carried without symptoms by the majority of the population. However, it can cause serious disease in infants born to mothers who acquire the infection in pregnancy and in people whose immune systems are suppressed, for instance when they undergo transplantation for an organ such as a kidney or bone marrow it can be life threatening. The fact that up to 3 people are dying a day because of a lack of a suitable transplant organs and this is resulting in a call for increases in the number of transplants in the UK (http://www.bbc.co.uk/news/health-11688102), HCMV disease is likely to become more and more of a problem in transplant patients.
Unlike many other viruses, HCMV is never cleared after its initial infection but persists for the life time of the individual. At least in part, this is due to the ability of HCMV to avoid the immune system by expression of virus genes which help it avoid immune responses. However, the lifelong persistence of this virus is also a biological property of all herpesviruses because the virus is able to undergo a so-called latent infection, where the virus hides in the cell without making new virus particles but is still able to reawaken, generating new infectious virtues which can cause disease and can also be passed on to other uninfected people.
Understanding how the virus succeeds in maintaining itself in most people without causing disease and how this relationship breaks down to cause disease should help develop better methods of treating the virus and for designing a vaccine (there is currently no vaccine available).
Our research is aimed at determining (i) the mechanism by which the virus maintains a silent infection (latency) in specialised cells of the immune system and how these help the virus reawaken (reactivation) and (ii) how the immune system is prevented from eliminating the virus from the body.
In addition to advancing our understanding of HCMV, in particular, this research may also lead to a better understanding of other virus infections which persist in the body, how the human host controls and help identify common strategies for their elimination.

Human cytomegalovirus (HCMV) primary infection of the immunocompetent is asymptomatic. However, infection of individuals with compromised or immature immune systems can be life threatening. Furthermore, HCMV persists for the lifetime of the host which, at least in part, is due to the ability of HCMV to avoid immunesurveillance and, ultimately,establish a latent infection. Cellular latency is defined as genome carriage with viral transcription limited to a few latency-associated genes and no infectious virus production. Consequently, current therapies targeting HCMV replication will not target the latent virus. However, viral reactivation from latency is a major cause of disease in immune suppressed transplant patients. Furthermore, there is increasing evidence associating HCMV with long-term diseases (i.e. atherosclerosis, chronic graft rejection and neoplasias) with reactivation of latent HCMV likely to be a major source of virus. Consequently, therapeutics that target latently infected cells could have far reaching clinical implications.
Work from our laboratory has been instrumental in identifying a subset of viral genes expressed during HCMV latency, the host immune responses to these latency-associated antigens,and how these genes modify the latently infected cell.In the case of expression of viral UL138 during latency, we have already identified changes in the latently infected cell mediated by UL138 expression allowing them to be targeted chemotherapeutically.
We propose to build on this work and comprehensively analyse the effects of expression of additional viral latency-associated genes on the cell and the immune response. Such analyses will allow a more comprehensive understanding of how this human pathogen persists for the lifetime of the host and also identify additional changes in the latently infected cell which can be further exploited for chemotherapeutic and immunological targets to lead to credible strategies aimed at eliminating latent virus.

Human cytomegalovirus (HCMV) is universally distributed in human populations and, like herpesviruses, persists throughout life following primary infection. HCMV remains an important human pathogen, particularly in the settings of congenital infection; it is the commonest infective cause of congenital central nervous system damage and a major cause of morbidity and mortality in immunocompromised subjects (Rubin Rev Infect Dis 1990. Drew Rev Infect Dis 1988), especially in the context of organ and bone marrow allografting. Whilst antiviral therapy is available, significant side effects and drug resistance occur. Additionally, treatment does not eliminate the virus which can subsequently reactivate and cause further morbidity. Consequently, HCMV headed the list of vaccines needed by the US in the report from the Institute of Medicine on Priorities for Vaccines (Arvin Clin Infect Dis 2004), in part reflecting the weighting this gave to quality life years saved.
Understanding virus pathogenesis at a molecular level during both lytic infection and latency, and thus how viral gene products interact with host immune responses, is crucial for rational design of therapeutics - both novel antiviral strategies and approaches to vaccines. For HCMV, this is increasingly important; not least because of the calls for transplant organs by the BMA and Government (http://www.bbc.co.uk/news/health-11688102) but also because there is increasing opinion that long-term persistence of HCMV, which encompasses reactivation from latency, is associated with long-term diseases such as atherosclerosis, chronic graft rejection and neoplasias.
This research will directly benefit research academics (UK and international) both in the herpesvirus community as well as communities interested in the mechanisms of immunity and immune evasion; providing immediate impact for the duration of the grant.
Similarly, the National Institute of Health Research (NIHR) community clearly benefits from any successful outcomes of the proposed research programme through decreased transplantation-mediated HCMV disease.The University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, as one of the 11 NIHR Comprehensive Biomedical Research Centres (BRC) in the UK, are ideally placed to adopt new insights in technologies, techniques and treatments for improving health and to translate fundamental biomedical research into clinical research that benefits patients: Infection & Immunity is one of the 11 themes in our BRC, which will help facilitate the translational research associated with this application.
We expect our research to inform industrial partners interested in vaccine and drug development as results from the proposed research will provide key information both for vaccine design and for drug targeting. For instance, a successful vaccine program of women prior to pregnancy will have very clear health impacts through the prevention of congenital infections and the subsequent long term health care costs associated with treating these patients.
Our proposed programme will support two technicians and two postdoctoral scientists, all of whom are supported by our present programme of work. Our long-term funding has allowed, and will continue to allow, our research technicians to become highly skilled laboratory workers. Their in-house training will also enable them to move into higher level managerial and teaching roles vital for the effective running of research groups and University Departments. The training that our post-doctoral researchers receive, not only in laboratory based research but also in undergraduate and PhD student teaching as well as oral and written presentational skills, will enable them to move on to academic posts to develop their own research programs as well as to become well trained scientists who would also be highly valued by industry.