Human herpesvirus biology. Most of us are infected with one or more of the eight known human herpesviruses. Although all herpesviruses establish incurable, life-long infections, they usually cause only mild if any symptoms in people with fully developed and healthy immune systems. However, herpesviruses can be dangerous pathogens under conditions of developmental or acquired immune deficiency. In fact, congenital infection with the human herpesvirus 5 or cytomegalovirus (CMV) is the leading cause of brain damage, hearing loss and other neurological disorders in children in the UK and far beyond. In addition, CMV causes disease and death in immune-suppressed people including transplant, AIDS, cancer and intensive care patients. Despite the considerable public health burden, there are few prevention and treatment options for CMV and other herpesviruses.
Epigenetic control of infection. Herpesviruses have large (by viral standards) double-stranded DNA genomes. Like our own genome, nuclear herpesvirus DNA forms nucleosomes (histone octamers wrapped by 147 base pairs of DNA) which are the basic building blocks of chromatin and the substrates of most epigenetic processes. Our work has contributed much to the current view of how nucleosomes are assembled and modified on CMV genomes to control viral transcription. We also identified a CMV gene product, the 72-kDa immediate-early 1 protein (IE1), which binds to the “acidic patch” formed by histones H2A and H2B on the surface of nucleosomes presumably to modulate chromatin function. Our ongoing work aims at further elucidating the chromatin-based epigenetic processes in viral and cellular chromatin that control the transcription, replication and repair of DNA to dictate the outcome of infection and disease (collaboration with Prof Eran Segal, Weizmann Institute of Science).
Innate immune signalling. Both acquired and innate immune mechanisms are thought to be vital for keeping CMV and other herpesviruses in check, so that they cannot make us sick. Arguably, our most powerful innate means to fight viruses is the interferon (IFN) response. Incidentally, the same CMV protein that proved to target nucleosomes (see above) also turned out to be a major antagonist of the IFN response. In fact, the viral IE1 protein confers type I IFN resistance to CMV by interacting with the human STAT2 protein, which is essential for type I signalling. Unlike other viral STAT2 antagonists, IE1 does not target STAT2 for degradation but re-localises the protein within the nucleus. IE1 also forms a complex with another STAT family member, STAT3, a critical mediator of signalling via interleukin 6 (IL6) and related cytokines. By targeting STAT3, IE1 rewires upstream STAT3 to downstream STAT1 signalling. Consequently, genes normally induced by IL6 are repressed while genes normally induced by IFNγ become responsive to IL6 in the presence of IE1. Thus IE1 rewires central STAT-dependent cellular signalling pathways to divert cytokine responses relevant to CMV pathogenesis.
Novel diagnostic, preventive and therapeutic strategies. As part of the “TargetHerpes” European consortium, we developed siRNA- and small molecule-based antiviral agents directed against IE1 and other CMV proteins not targeted by currently available drugs. Ongoing work aims at exploiting the IFN antagonist function of IE1 to identify innovative antiviral compounds (collaboration with Dr Cathy Adamson and Prof Rick Randall, University of St Andrews). We have also been exploring the feasibility of “epigenetic therapies” for CMV and other virus infections. Moreover, our work has contributed to the development of T-Track® CMV, a kit for quantification of CMV-specific immune cells from patient blood, by Lophius Biosciences (Germany). The kit employs purified CMV pp65 and IE1 proteins specifically formulated to allow for in vitro re-stimulation of peripheral blood mononuclear cells in a largely HLA-independent fashion. Reactivated cells are subsequently quantified by IFNγ-based ELISpot technology. The kit is currently evaluated in phase 2 clinical trials and will be further developed for routine use to monitor cell-based anti-CMV immune responses in solid organ and bone marrow transplant patients. Finally, our work has contributed to the development of the Redvax CMV vaccine platform by Redbiotec (Switzerland), sold to Pfizer in 2014.
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