Host-pathogen interactions, and Cytomegalovirus latency and pathogenesis.
Human Cytomegalovirus (HCMV) remains a major clinical complication in a number of settings including immune-suppressed transplant patients and following congenital infection. The ability of HCMV, like all herpes viruses, to establish a lifelong latent infection of the host results in the threat posed by HCMV as twofold: Transplant patients are at risk following primary infection or following the reactivation of the latent virus that resides in the recipient.
Our group is part of the CMV research group (with Prof Griffiths) and is focussed on dissecting the molecular basis of HCMV latency and reactivation as well as the role of host cell functions during lytic infection. Specifically, we are investigating the contribution of both viral and cellular functions to the maintenance of latency with particular emphasis on how cell signalling pathways are important during both the establishment and reactivation of the latent infection.
Alongside these studies we investigate the natural history of HCMV in solid organ transplant patients. Here the focus is to understand the role of viral genetics and host immunity in the onset of viraemia in these patients with a view to a clearer understanding of why certain individuals are at increased risk of HCMV pathogenesis.
It is hoped that a thorough understanding of the HCMV biology and pathogenesis will be instructive for our ongoing efforts to develop new vaccination strategies against HCMV.
- Selected publications
- Mason R, Groves IJ, Wills MR, Sinclair JH, Reeves MB. Human cytomegalovirus major immediate early transcripts arise predominantly from the canonical major immediate early promoter in reactivating progenitor-derived dendritic cells. J Gen Virol. 2020 Jun;101(6):635-644. doi: 10.1099/jgv.0.001419. PMID: 32375946
- Murray MJ, Bonilla-Medrano NI, Lee QL, Oxenford SJ, Angell R, Depledge DP, Reeves MB. Evasion of a Human Cytomegalovirus Entry Inhibitor with Potent Cysteine Reactivity Is Concomitant with the Utilization of a Heparan Sulfate Proteoglycan-Independent Route of Entry. J Virol. 2020 Mar 17;94(7):e02012-19. doi: 10.1128/JVI.02012-19. PMID: 31941787; PMCID: PMC7081914
- Baraniak I, Gomes AC, Sodi I, Langstone T, Rothwell E, Atkinson C, Pichon S, Piras-Douce F, Griffiths PD, Reeves MB. Seronegative patients vaccinated with cytomegalovirus gB-MF59 vaccine have evidence of neutralising antibody responses against gB early post-transplantation. EBioMedicine. 2019 Dec;50:45-54. doi: 10.1016/j.ebiom.2019.11.005. Epub 2019 Nov 15. PMID: 31735553; PMCID: PMC692136
- Dupont L, Du L, Poulter M, Choi S, McIntosh M, Reeves MB. Src family kinase activity drives cytomegalovirus reactivation by recruiting MOZ histone acetyltransferase activity to the viral promoter. J Biol Chem. 2019 Aug 30;294(35):12901-12910. doi: 10.1074/jbc.RA119.009667. Epub 2019 Jul 4. PMID: 31273084; PMCID: PMC6721939
- Baraniak I, Kern F, Holenya P, Griffiths P, Reeves M. Original Antigenic Sin Shapes the Immunological Repertoire Evoked by Human Cytomegalovirus Glycoprotein B/MF59 Vaccine in Seropositive Recipients. J Infect Dis. 2019 Jun 19;220(2):228-232. doi: 10.1093/infdis/jiz089. PMID: 30815685; PMCID: PMC6581893
- Poole EL, Kew VG, Lau JCH, Murray MJ, Stamminger T, Sinclair JH, Reeves MB. A Virally Encoded DeSUMOylase Activity Is Required for Cytomegalovirus Reactivation from Latency. Cell Rep. 2018 Jul 17;24(3):594-606. doi: 10.1016/j.celrep.2018.06.048. PMID: 30021158; PMCID: PMC6077246
- Baraniak I, Kropff B, Ambrose L, McIntosh M, McLean GR, Pichon S, Atkinson C, Milne RSB, Mach M, Griffiths PD, Reeves MB. Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies. Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6273-6278. doi: 10.1073/pnas.1800224115. Epub 2018 Apr 23. PMID: 29686064; PMCID: PMC6004462
Also see editorial: Schleiss MR. Recombinant cytomegalovirus glycoprotein B vaccine: Rethinking the immunological basis of protection. Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):6110-6112. doi: 10.1073/pnas.1806420115. Epub 2018 Jun 6. PMID: 29875141; PMCID: PMC6004476
- Baraniak I, Kropff B, McLean GR, Pichon S, Piras-Douce F, Milne RSB, Smith C, Mach M, Griffiths PD, Reeves MB. Epitope-Specific Humoral Responses to Human Cytomegalovirus Glycoprotein-B Vaccine With MF59: Anti-AD2 Levels Correlate With Protection From Viremia. J Infect Dis. 2018 May 25;217(12):1907-1917. doi: 10.1093/infdis/jiy102. PMID: 29528415; PMCID: PMC5972559
- Kew VG, Yuan J, Meier J, Reeves MB. Mitogen and stress activated kinases act co-operatively with CREB during the induction of human cytomegalovirus immediate-early gene expression from latency. PLoS Pathog. 2014 Jun 12;10(6):e1004195. doi: 10.1371/journal.ppat.1004195
- Huang MM, Kew VG, Jestice K, Wills MR, Reeves MB. 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. 2012 Aug;86(16):8507-15. doi: 10.1128/JVI.00598-12. Epub 2012 May 30. PMID: 22647696; PMCID: PMC3421708
- Reeves MB, Breidenstein A, Compton T. Human cytomegalovirus activation of ERK and myeloid cell leukemia-1 protein correlates with survival of latently infected cells. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):588-93. doi: 10.1073/pnas.1114966108. Epub 2011 Dec 27. PMID: 22203987; PMCID: PMC3258610
- Reeves MB, Compton T. Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. J Virol. 2011 Dec;85(23):12750-8. doi: 10.1128/JVI.05878-11. Epub 2011 Sep 21. PMID: 21937636; PMCID: PMC3209367
- Reeves MB, Davies AA, McSharry BP, Wilkinson GW, Sinclair JH. Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death. Science. 2007 Jun 1;316(5829):1345-8. doi: 10.1126/science.1142984. PMID: 17540903
- Reeves MB, MacAry PA, Lehner PJ, Sissons JG, Sinclair JH. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4140-5. doi: 10.1073/pnas.0408994102. Epub 2005 Feb 28. PMID: 15738399; PMCID: PMC554799
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