School of Medicine

Date

9th June 2010

HCMV is ubiquitous in human populations worldwide. 

While the vast majority of infections are not associated with overt clinical disease, HCMV produces severe life-threatening infections in immunosuppressed transplant recipients and during the later stages of HIV AIDS. HCMV is also a causative agent of infectious mononucleosis, colitis, hepatitis and post-transplant arteriosclerosis. 

Transplacental transmission can result in spontaneous abortion, overt cytomegalic inclusion disease at birth and neurological damage, which manifest as deafness or learning disability in early life. The long-term consequences of congenital HCMV infection was highlighted in a US Institute of Medicine report that designated HCMV a highest priority (level 1) vaccine target. Recent studies have detected HCMV IE gene expression in up to 90% of malignant gliomas. Furthermore, asymptomatic carriage may potentially be harmful. Seroconversion correlates with alterations to the T and NK cell repertoires. Following lifelong persistent antigenic stimulation, HCMV-specific T lymphocytes can dominate the CTL response: an effect that has been linked with immune senescence in the elderly. HCMV is the most complex of any human virus. An enhanced understanding of HCMV pathogenesis is urgently needed to underpin the development of safe and efficacious immunotherapeutic, vaccine and antiviral strategies.

Natural Killer (NK) cells are recognised to play a crucial role in the control of HCMV infection, a correlation that is strongly reinforced with elegant studies performed in the murine CMV model. The extreme divergence of the NK response in mouse and man, and their corresponding viruses, necessitates pathogenesis study be performed with HCMV itself. NK cells constitute a heterogeneous population of cells expressing a complex and variable array of NK activating and inhibitory receptors. The remarkable resistance of cells infected with low-passage HCMV strains to NK cell-mediated cytolysis is dependent absolutely on protection bestowed by virus-encoded NK modulators. Research from our previous Wellcome Trust Programmes identified or further characterised 4 of the 7 currently recognised NK evasion functions (Tomasec et al., 2000; Wang et al., 2002; Morris et al., 2005; Tomasec et al., 2005; Griffin et al., 2005; Wills et al., 2005; Prod’homme et al., 2007; Wilkinson et al., 2008), but ongoing studies indicate many more exist. In this extended Programme of work, we seek to map and characterise all HCMV NK modulatory functions, which will not only lead to a better understanding of HCMV pathogenesis but also will generate reagents that enable a systematic dissection and evaluation of human NK cell function.

References

^{(* = joint first author)}

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• *Prod’homme V, *Griffin C, Aicheler RJ, Wang EC, McSharry BP, Rickards CR, Stanton R, Borysiewicz LK, Lopez-Botet M, Wilkinson GW, Tomasec P (2007) The human cytomegalovirus MHC class I homologue UL18 inhibits LIR-1⁺ but activates LIR-1^- natural killer cells. Journal of Immunology 178: 4473-4481.
• Wills MR, Ashiru O, Reeves MB, Okecha G, Trowsdale J, Tomasec P, Wilkinson GW, Sinclair J, Sissons JG (2005) Human cytomegalovirus encodes an MHC class I-like molecule (UL142) that functions to inhibit NK cell lysis. Journal of Immunology 178: 4473-4481.
• Griffin CA, Wang EC, McSharry BP, Rickards C, Browne H, Wilkinson GW, Tomasec P (2005) Characterisation of a highly glycosylated form of the human cytomegalovirus MHC class I homologue gpUL18. Journal of General Virology 86: 2999-3008.
• *Tomasec P, *Wang EC, Davison AJ, Vojtesek B, Armstrong M, Griffin C, McSharry BP, Morris RJ, Llewellyn-Lacey S, Rickards C, Nomoto A, Sinzger C, Wilkinson GW (2005) Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirus UL141. Nature Immunology 6: 181-188.
• Morris RJ, Chong LK, Wilkinson GW, Wang EC (2005) A high-efficiency system of natural killer cell cloning. Journal of Immunological Methods 307: 24-33.
• *Wang EC, *McSharry B, Retiere C, Tomasec P, Williams S, Borysiewicz LK, Braud VM, Wilkinson GW (2002) UL40-mediated NK evasion during productive infection by human cytomegalovirus. Proceedings of the National Academic Science, USA 99: 7570-7575.
• Tomasec P, Braud VM, Rickards C, Powell MB, McSharry BP, Gadola S, Cerundolo V, Borysiewicz LK, McMichael AJ, Wilkinson GW (2000) Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287: 1031.