Biology of cytomegalovirus in the human host: cellular and immunological control

Lead Research Organisation: University of Cambridge
Department Name: Medicine

Abstract

Human cytomegalovirus (HCMV) is a virus 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 system is suppressed. 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 of designing a vaccine (there is currently no vaccine available). Our research is aimed at determining (i) how the virus gains control of the cell in order to reproduce itself (ii) the mechanism by which the virus maintains silent infection ( latency ) in specialised cells of the immune system and the factors that reawake it and (iii) how the immune system controls the infection in normal people. We shall then extend our work to try and generate useful immune responses in patients at risk of infection. 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, and how the human host controls them.

Technical Summary

This programme of research focuses on human cytomegalovirus (HCMV) a ubiquitous human herpesvirus which is a major cause of morbidity, especially in the immunocompromised host.
Understanding the molecular interactions between the virus and the cell which maintain latency and permit reactivation, and how the immune response then limits dissemination, are fundamental to understanding viral pathogenesis. Myeloid lineage cells are now established as being of major importance in carriage of the virus in vivo: our work has now shown that their differentiation to dendritic cells plays an integral role in reactivation of latent HCMV, and that human dendritic cells are a tractable model system in which to analyse reactivation of endogenous latent virus. The proposed work will concentrate on three main areas: (i) The mechanism by which differentiation-specific cellular factors maintain latency by repressing lytic gene expression in myeloid cells and the means by which the major viral lytic genes, once expressed, interdict in normal cell cycle control. (ii) The analysis of latency and reactivation of endogenous HCMV in a new model system we have identified, dendritic cells. (iii) The mechanism by which CD8+ T cell memory to HCMV is generated in primary infection and subsequently maintained, and how expression of specific HCMV proteins may influence and modulate the response. This work should lead to a more detailed understanding of virus latency and reactivation in the human host and hence to more rational interventional strategies.

Publications

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Bennett NJ (2010) Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus. in Journal of immunology (Baltimore, Md. : 1950)

 
Description Programme grant renewal
Amount £1,900,000 (GBP)
Funding ID G0701279 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2008 
End 11/2013
 
Title Model sysytems for cytomegalovirus latency 
Description CD34+ progenitor cells latently infected with cytomegalovirus 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2009 
Provided To Others? Yes  
Impact Other research groups are using thsi model system 
 
Title Novel detection systems for latent infection 
Description New targets to detect latently infected cells by PCR 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact none as yet 
 
Title mutant viruses 
Description Recombinant viral mutants deficient in latent gene expression 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact none as yet 
 
Description Analysis of latency-associated transcripts 
Organisation Cleveland Clinic
Department Cleveland Clinic Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution Our research led to the detection of certain viral genes during latent infection
Collaborator Contribution Our collaborators helped us to define latent transcripts further work on which was funded by an MRC Programme Grant renewal
Impact Betty Lau, Emma Poole, Ellen Van Damme, Lieve Bunkens, Madeleine Sowash, Harry King, Eain Murphy, Mark Wills, Marnix Van Loock, John Sinclair 2016. Human cytomegalovirus miR-UL112-1 promotes the down-regulation of viral immediate early gene expression during latency to prevent T cell recognition of latently infected cells Published ahead of print 10.1099/jgv.0.000546 Betty Lau, Emma Poole, Benjamin Krishna, Immaculada Sellart, Mark R. Wills, Eain Murphy, and¬ John Sinclair (2016) The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL-6. Sci Rep. 6 :31205, doi:10.1038/srep31205
Start Year 2013
 
Description Single Cell RNAseq of latently infected cells 
Organisation Weizmann Institute of Science
Country Israel 
Sector Academic/University 
PI Contribution We provide sorted latently infected CD34 and CD14 positive cells for RNAseq
Collaborator Contribution RNA sequencing of latently infected cells
Impact None, yet
Start Year 2015
 
Description Oral presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact University of Cambridge Science Festival

Dissemination of the research to the public
Year(s) Of Engagement Activity 2008
 
Description University of Cambridge Public Understanding of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Lecture to attendees

None
Year(s) Of Engagement Activity 2006