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  • Review Article
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Oncogenic γ-herpesviruses: comparison of viral proteins involved in tumorigenesis

Nature Reviews Microbiology volume 2, pages 656–668 (2004)Cite this article

Key Points

  • The double-stranded DNA herpesviruses are classified into three subfamilies: α, β and γ. The γ-herpesviruses, which have been identified in many animal species, are lymphotropic and can establish a lifelong period of latency in their host, with intermittent periods of lytic replication.

  • This article focuses on three γ-herpesviruses, EBV, KSHV and HVS. KSHV and EBV infect humans, whereas the natural host for HVS is the squirrel monkey. The g-herpesviruses encode proteins that modulate signalling pathways, transform cells and also play a role in virus survival in the host environment. The genomes of EBV, KSHV and HVS contain an open-reading frame (ORF) at the 5'-end that possesses transforming potential. This ORF encodes latent membrane protein 1 (LMP1) in EBV, K1 in KSHV and STP in HVS. Each of these gene products is involved in activating B- or T-cell signal transduction pathways. Other important signal-modulatory proteins include EBV LMP2A, KSHV K15 and HVS Tip, a protein only found in HVS subgroup C. These gene products can inhibit signal transduction by the BCR (LMP2A and K15) and TCR (Tip). In addition, many other viral proteins are involved in the modulation of cellular signalling pathways, including EBV EBNA-2 and EBNA-3 gene products, and KSHV vGPCR and Kaposin.

  • During latent infection, the γ-herpesviruses express a small number of genes, some of which are required to maintain the viral genome in the episomal form and to support latent viral replication. The EBNA-1, LANA and ORF73 proteins of EBV, KSHV and HVS, respectively, perform this important function.

  • Viral cytokines that show sequence similarity to cellular cytokines play a role in cell proliferation and also contribute to virus survival within the host environment by allowing the virus to evade the host immune-surveillance machinery. Examples of these gene products include KSHV vIL-6, HVS vIL-17, EBV vIL-10 and the KSHV vCCLs.

Abstract

Herpesviruses are present in most species throughout the animal kingdom and are classified into three subfamilies, α, β and γ, on the basis of their biological properties and genome sequences. A striking feature that is shared by many of the γ-herpesviruses is their ability to induce neoplastic disease in the host. This review focuses on three γ-herpesviruses: Epstein–Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV) and herpesvirus saimiri (HVS), and discusses the diverse array of EBV, KSHV and HVS viral genes that are involved in transformation, cell signalling, episomal maintenance and cell proliferation.

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Figure 1: A phylogenetic tree representing the γ-herpesviruses Epstein-Barr virus (EBV), Kaposi's sarcoma-associated virus (KSHV) and herpesvirus saimiri (HVS).
Figure 2: Alignment of the genomes of three γ-herpesviruses: Epstein–Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV) and herpesvirus saimiri (HVS).
Figure 3: Transforming proteins encoded by the first open reading frames of the γ-herpesviruses EBV, KSHV and HVS.
Figure 4: Cellular effects of the signal modulatory proteins EBV LMP2A, KSHV K15 and HVS TIP.
Figure 5: Viral cytokines and chemokines encoded by EBV, KSHV and HVS.

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GenBank/EMBL/DDBJ

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Acknowledgements

The author would like to thank D. P. Dittmer for critical reading of the manuscript. The author is supported by grants from the American Association for Cancer Research (Gertrude B. Elion Research Award), American Heart Association and NIH/NCI.

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  1. Department of Microbiology & Immunology, Lineberger Comprehensive Cancer Center, CB #7295, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Blossom Damania

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DATABASES

Entrez

EBV

HCMv

HHV-6

HHV-7

HSV-1

HSV-2

KSHV

MMP-9

NF-κB

PI3K

VZV

SwissProt

Kaposin

LANA

LMP1

LYN

FURTHER INFORMATION

Blossom Damania's laboratory

Glossary

NEOPLASIA

Abnormal new growth of cells in the process of tumour formation.

PARACRINE

A substance that is secreted by a cell and which acts on neighbouring cells

LYMPHOMA

A general term for cancers that develop in the lymphatic system.

LYMPHOSARCOMA

A malignant lymphoma.

LEUKAEMIA

Cancer of white blood cells.

LYMPHOBLASTOID CELL LINES

Virally infected lymphocytes propagated in tissue culture become enlarged, appear activated, and continuously divide.

PLASMABLASTIC LYMPHOMAS

A form of malignant B-cell lymphoma in which the cells resemble antibody-secreting plasma cells.

MULTICENTRIC CASTLEMAN'S DISEASE

A rare B-cell lymphoproliferative disorder.

PRIMARY EFFUSION LYMPHOMAS

A subset of malignant B-cell lymphomas that localize to body cavities such as the pleura, peritoneum or pericardium.

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Damania, B. Oncogenic γ-herpesviruses: comparison of viral proteins involved in tumorigenesis. Nat Rev Microbiol 2, 656–668 (2004). https://doi.org/10.1038/nrmicro958

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