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Viral latency drives ‘memory inflation’: a unifying hypothesis linking two hallmarks of cytomegalovirus infection

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Abstract

Low public awareness of cytomegalovirus (CMV) results from the only mild and transient symptoms that it causes in the healthy immunocompetent host, so that primary infection usually goes unnoticed. The virus is not cleared, however, but stays for the lifetime of the host in a non-infectious, replicatively dormant state known as ‘viral latency’. Medical interest in CMV results from the fact that latent virus can reactivate to cytopathogenic, tissue-destructive infection causing life-threatening end-organ disease in immunocompromised recipients of solid organ transplantation (SOT) or hematopoietic cell transplantation (HCT). It is becoming increasingly clear that CMV latency is not a static state in which the viral genome is silenced at all its genetic loci making the latent virus immunologically invisible, but rather is a dynamic state characterized by stochastic episodes of transient viral gene desilencing. This gene expression can lead to the presentation of antigenic peptides encoded by ‘antigenicity-determining transcripts expressed in latency (ADTELs)’ sensed by tissue-patrolling effector-memory CD8 T cells for immune surveillance of latency [In Reddehase et al., Murine model of cytomegalovirus latency and reactivation, Current Topics in Microbiology and Immunology, vol 325. Springer, Berlin, pp 315–331, 2008]. A hallmark of the CD8 T cell response to CMV is the observation that with increasing time during latency, CD8 T cells specific for certain viral epitopes increase in numbers, a phenomenon that has gained much attention in recent years and is known under the catchphrase ‘memory inflation.’ Here, we provide a unifying hypothesis linking stochastic viral gene desilencing during latency to ‘memory inflation.’

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Acknowledgments

We thank all current and former members of our group for their contributions made over the past 12 years as well as our collaboration partners Ulrich H. Koszinowski (Munich, Germany), Martin Messerle (Hannover, Germany), Ann B. Hill and Michael Munks (Portland, Oregon), Peter Ghazal (Edinburgh, Scotland), and Stipan Jonjic (Rijeka, Croatia) for advice, discussion, and tools. We appreciated the excellent service provided by Dennis Strand and Steffen Lorenz, ‘Confocal Laser Scanning Microscope Core Facility’ of the ‘Immunology Research Center’ at the University Medical Center of the Johannes Gutenberg-University Mainz. This work was funded by the Deutsche Forschungsgemeinschaft, SFB 490, individual project E2 ‘Immunological control of latent cytomegalovirus infection.’ C.K.S. received intramural funding in the young investigator program MAIFOR of the University Medical Center of the Johannes Gutenberg-University, Mainz. J.K.B. received a ‘Gender Equality Program’ scholarship from the ‘Immunology Research Center’ (Forschungszentrum Immunologie, FZI).

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  1. Institute for Virology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131, Mainz, Germany

    Christof K. Seckert, Marion Grießl, Julia K. Büttner, Sabine Scheller, Christian O. Simon, Kai A. Kropp, Angélique Renzaho, Birgit Kühnapfel, Natascha K. A. Grzimek & Matthias J. Reddehase

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  1. Christof K. Seckert
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  2. Marion Grießl
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  3. Julia K. Büttner
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  4. Sabine Scheller
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  5. Christian O. Simon
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  6. Kai A. Kropp
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  7. Angélique Renzaho
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  8. Birgit Kühnapfel
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  9. Natascha K. A. Grzimek
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  10. Matthias J. Reddehase
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Corresponding author

Correspondence to Matthias J. Reddehase.

Additional information

Christof K. Seckert, Marion Grießl and Julia K. Büttner have contributed equally.

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Seckert, C.K., Grießl, M., Büttner, J.K. et al. Viral latency drives ‘memory inflation’: a unifying hypothesis linking two hallmarks of cytomegalovirus infection. Med Microbiol Immunol 201, 551–566 (2012). https://doi.org/10.1007/s00430-012-0273-y

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  • DOI: https://doi.org/10.1007/s00430-012-0273-y

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