MRC Career Development Fellow
Tel: +44 1223 336862
Human cytomegalovirus (HCMV) is an opportunistic pathogen that is a significant cause of morbidity and mortality in immune-compromised individuals. Like all herpesviruses, HCMV establishes a lifelong latent infection in the host and a major site of latency is the cells of the myeloid lineage; latency being established in a sub-population of CD34+ progenitor cells in the bone marrow. Only upon normal differentiation of these cells to macrophages or dendritic cells (DCs) is reactivation detected. Consequently, it is hypothesised that changes in the cellular environment concomitant with differentiation also promote reactivation.
My research focus is to identify and characterise cellular signalling pathways important during HCMV latency and reactivation. Specifically, a major focus is the delineation of signalling pathways activated during DC maturation that are also responsible for reactivation. With particular emphasis on the upstream molecular cues responsible – notably inflammatory cues. Currently, we are seeking to understand the signalling events associated with IL-6 that are important for reactivation and the interplay between IL-6, ERK-MAPK and further secondary pathways recently identified. Furthermore, future work aims to elucidate the specific cellular factors that are key players in the utilisation of this pathway to promote reactivation.
A second goal is to characterise the enzymatic function and putative viral or cellular targets of the Latent Undefined Nuclear Antigen (LUNA). Many protein functions are regulated post-translationally thus the expression of LUNA could provide HCMV the means to manipulate a number of host pathways during all phases of infection.
Finally, we are also beginning to address the impact of cellular signalling during the initial phases of HCMV latent infection of CD34+ cells and how signalling events associated with binding and entry may play a role in the establishment of HCMV latency.
These studies form part of a major research theme within the infectious disease group seeking to understand the fundamental aspects of HCMV biology at a molecular, cellular and immunological level.
Reeves M.B. & Compton T. (2011) Inhibition of inflammatory interleukin-6 activity via extracellular signal regulated mitogen activated protein kinase signalling antagonizes human cytomegalovirus reactivation from dendritic cells. J. Virol. 85(23):12750-8
Reeves M.B., MacAry P.A., Lehner P.J., Sissons J.G.P. and Sinclair J.H. (2005) Latency, chromatin remodeling and reactivation of HCMV in the dendritic cells of healthy carriers. Proc. Natl. Acad. Sci. USA 102(11): 4140-5
Reeves M.B., Breidenstein A., Marty F. & Compton T. (2012) Human Cytomegalovirus activation of ERK and myeloid cell leukaemia-1 protein correlates with survival of latently infected cells. Proc. Natl. Acad. Sci. USA 109(2):588-93.
- Huang M.M., Kew V.G., Jestice K., Wills M.R. & Reeves M.B. (2012) Efficient human cytomegalovirus reactivation is maturation dependent in the Langerhans dendritic cell lineage and can be studied using a CD14+ experimental latency model. J. Virol. 86(16): 8507-15
- Reeves M.B. (2011) Chromatin mediated regulation of cytomegalovirus gene expression. Virus Research. 157(2): 134-43
- Reeves M.B., Woodhall D.L., Compton T.G. & Sinclair J.H. (2010) Human Cytomegalovirus protein IE72 interacts with the transcriptional repressor hDaxx to regulate LUNA gene expression during lytic infection. J. Virol. 84(14): 7185-94
- Reeves M.B. & Sinclair J.H. (2009) Analysis of latent viral gene expression in natural and experimental latency models of human cytomegalovirus and its correlation with histone modifications at a latent promoter J. Gen. Virol. 91(3): 599-604
- Groves I.J., Reeves M.B. and Sinclair J.H. (2009) The regulation of HCMV gene expression by chromatinisation during productive infection of fibroblasts. J. Gen. Virol. 90(10): 2364-74
- Reeves M.B. and Sinclair J.H. (2008) Aspects of Human Cytomegalovirus latency. In Current Topics in Microbiology and Immunology Springer Press (Eds. M. Stinski and T Shenk). 325: 297-313
- Reeves M.B., Davies A.A., McSharry B.P., Wilkinson G.W. and Sinclair J.H. (2007) A virally encoded RNA molecule protects infected cells from mitochondrial-induced cell death. Science 316(5829): 1345-8 see also Perspectives section in Science 317(5836): 329-30
- Goodrum F, Reeves M.B., Sinclair J.H., High K. and Shenk T (2007) Human Cytomegalovirus UL138 gene promotes latency. Blood 110(3): 937-45
- Woodhall D.L., Groves I.J., Reeves M.B., Wilkinson G.W. and Sinclair J.H. (2006) hDaxx mediated repression of human cytomegalovirus gene expression correlates with a repressive chromatin structure around the major immediate early promoter. J. Biol. Chem. 281(49): 37652-60
- Reeves M.B., Murphy J.C., Greaves R.J. Fairley J.A., Brehme A. and Sinclair J.H. (2006) Auto-regulation of the HCMV MIEP by IE86 is mediated by recruitment of chromatin remodeling enzymes. J. Virol. 80(20): 9998-10009
- Wills M.R., Ashiru O., Reeves M.B., Okecha G, Trowsdale J., Tomasec P.T., Wilkinson G.W.G., Sinclair J. and Sissons J.G.P. (2005) Human Cytomegalovirus encodes an MHC class I like molecule (UL142) which functions to inhibit natural killer (NK) cell lysis. J. Immunol 175 (11): 7457-65.
- Reeves M.B., Lehner P.J.,Sissons J.G.P. and Sinclair J.H. (2005) An in vitro model for the regulation of HCMV latency and reactivation in dendritic cells by chromatin remodeling. J. Gen. Virol 86(11): 2949-54
- Reeves M.B., Coleman H., Chadderton J., Goddard M., Sissons J.G.P and Sinclair J.H. (2004) Vascular endothelial and smooth muscle cells are unlikely to be major sites of HCMV latency in vivo. J. Gen. Virol. 85: 3337-41