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  • Review Article
  • Published:

Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance

Nature Reviews Immunology volume 2, pages 831–844 (2002)Cite this article

Key Points

  • Human cytomegalovirus is a medically relevant pathogen that affects newborns and immunocompromised individuals, such as AIDS patients and recipients of organ allografts or of bone-marrow transplants.

  • A vaccine aimed at preventing congenital infection could prevent neurological sequelae, such as mental retardation, hearing loss and blindness, in tens of thousands of children annually and, in addition, save the costs of health care.

  • Human and murine cytomegaloviruses both encode a set of glycoproteins, known as immunoevasins, the only known function of which is to prevent the presentation of antigenic peptides by the MHC class I pathway of antigen processing and presentation. Although the goal of the two viruses is the same, the molecular mechanisms by which the immunoevasins operate differ in their specific details.

  • The existence of immunoevasins might lead to the conclusion that vaccination aimed at inducing CD8+ T-cell-based immunity will fail. However, data from the mouse model, as well as clinical trials of adoptive cytoimmunotherapy of cytomegalovirus disease, indicate that there is immune surveillance of cytomegaloviruses, primarily by CD8+ T cells.

  • With one exception, immunoevasins are expressed in the second temporal phase of cytomegalovirus gene expression, known as the early (E) phase. Antiviral protection by CD8+ T cells might be explained by the recognition of antigenic peptides derived from the immediate-early 1 (IE1) protein, which is an immunodominant antigen of human and murine cytomegaloviruses that is expressed before the immunoevasins.

  • Recent data from the mouse model unexpectedly showed the existence of antigenic peptides derived from several E-phase proteins also. In my opinion, antigenic peptides that are presented constitutively in the face of viral immunoevasin functions are promising vaccine candidates.

Abstract

CD8+ T cells are the main effector cells for the immune control of cytomegaloviruses. To subvert this control, human and mouse cytomegaloviruses each encode a set of immune-evasion proteins, referred to here as immunoevasins, which interfere specifically with the MHC class I pathway of antigen processing and presentation. Although the concerted action of immunoevasins prevents the presentation of certain viral peptides, other viral peptides escape this blockade conditionally or constitutively and thereby provide the molecular basis of immune surveillance by CD8+ T cells. The definition of viral antigenic peptides that are presented despite the presence of immunoevasins adds a further dimension to the prediction of protective epitopes for use in vaccines.

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Figure 1: Molecular biology of the murine cytomegalovirus IE1 peptide.
Figure 2: Testing for antiviral activity of CD8+ T cells in vivo.
Figure 3: Models proposed for the action of immunoevasins.
Figure 4: Proposed mechanisms by which antigens evade immunoevasins.

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Acknowledgements

I apologize to all colleagues whose publications have not been included owing to space constraints and the focus of the review. I also apologize to colleagues who might have published peptide sequences (Table 2) that did not come to my attention. I thank U. H. Koszinowski, who brought me into CMV research and who was my scientific mentor for many years. I greatly appreciate the advice given by R. S. Lawrence regarding Box 2, and by P.-M. Kloetzel, H.-G. Rammensee and N. Shastri regarding Fig. 1. My co-workers J. Podlech and C. O. Simon did a perfect job with the design of the figures. Our recent work has been funded by the Deutsche Forschungsgemeinschaft.

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  1. Institute for Virology, Johannes Gutenberg University, Hochhaus am Augustusplatz, Mainz, 55101, Germany

    Matthias J. Reddehase

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  1. Matthias J. Reddehase
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DATABASES

Entrez

hCMV

IE1

m152

mCMV

rat cytomegalovirus

LocusLink

IFN-γ

TAP1

TAP2

FURTHER INFORMATION

Institute of Medicine

Vaccines for the 21st Century: A Tool for Decision-Making

SYFPEITHI Database for MHC-Binding Motifs

Institute for Virology, Johannes Gutenberg-University

Glossary

LATENCY

State of an infection that is characterized by the maintenance of replication-competent viral genomes in the absence of infectious virus particles. Although the viral replication cycle is not completed during latency, the viral genome is not necessarily transcriptionally silent. Potentially, a limited set of proteins is synthesized, and antigenic peptides can be presented for immune surveillance.

ANTIVIRAL CYTOIMMUNOTHERAPY

Prevention or treatment of viral disease in a recipient by the adoptive transfer of immune cells, usually by intravenous infusion of the cells.

PRE-EMPTIVE CYTOIMMUNOTHERAPY

Immune cells are adoptively transferred after molecular diagnosis of the infection, but before clinical symptoms of disease have developed.

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Reddehase, M. Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2, 831–844 (2002). https://doi.org/10.1038/nri932

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