Themed issue: the biology and pathology of the Epstein-Barr virus.

Based on their genomic organisation, tissue tropism, and other biological characteristics, herpesviruses are classified into three categories: á, â, and ã. Of these, the ã-herpesviruses are able to replicate and persist in lymphoid cells and some are capable of infecting other cell types, such as epithelial cells and fibroblasts. The ã-herpesviruses comprise two important genera: the lymphocryptoviruses (also referred to as ã-1 herpesviruses) and the rhadinoviruses (ã-2 herpesviruses). This themed issue principally concerns the biology and pathological eVects of one of the human ã-herpesviruses— the Epstein-Barr virus (EBV)—which is a ã-1 herpesvirus carried by over 90% of the world’s adult population as a lifelong asymptomatic infection. EBV is of particular interest to cell biologists, virologists, and pathologists alike because it is epidemiologically, serologically, and directly (by virtue of the detection of the virus genome and gene products in tumour cells) linked to a variety of human cancers. EBV associated cancers include several lymphoid disorders (Burkitt’s lymphoma, Hodgkin’s disease, post transplantation/human immunodeficiency virus associated lymphoproliferative disease, and some T cell lymphomas) and epithelial tumours (nasopharyngeal carcinoma and gastric carcinoma). All of these tumours are characterised by the presence of multiple extrachromosomal copies of the circular viral genome (episome) in every tumour cell and the expression of EBV encoded latent genes, which contribute to the malignant phenotype. The challenge is to understand the role of this virus in the development of its associated malignancies in the hope that this will provide alternative means to prevent or treat these tumours. In the opening article in this issue, John Nicholas overviews the organisation of ã-herpesvirus genomes and discusses mechanisms of genomic variation between diVerent virus groups. The ã-herpesvirus genomes are organised into blocks of genes that are conserved across all ã-herpesviruses. These so called “core” genes include those that function as “housekeeping” genes, often encoding proteins that are crucial for infection, virus replication, or virion assembly, which explains why they are so well conserved. Other ã-herpesvirus genes may be regarded as subfamily specific (that is, confined to only ã-1 or ã-2 viruses) or virus specific (that is, unique or partially conserved genes). This latter group includes cellular homologues that have been acquired relatively recently (in evolutionary terms) or ancient genes that have been lost by other members of the subfamily. Genomic similarities and diVerences between the ã-herpesviruses are well illustrated by comparing the EBV genome with that of another important oncogenic herpesvirus, the Kaposi’s sarcoma associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), which is a ã-2 virus. KSHV is associated with the development of Kaposi’s sarcoma and two rare lymphoproliferative diseases, multicentric Castleman’s disease and pleural eVusion lymphoma. The EBV and KSHV genomes have several genes with sequence/functional similarities. Thus, the EBV encoded nuclear antigen 1 (EBNA1) protein and the KSHV encoded latency associated nuclear antigen (LNA or LANA) are related nuclear proteins that play essential roles in episome maintenance and virus replication. Likewise, the EBV latent membrane protein 2 (LMP2) gene and the KSHV K15 gene are located at similar genomic locations (when the linear genomes are compared alongside each other) and both encode proteins containing 12 transmembrane domains, which function to inhibit B cell receptor signalling and thereby maintain virus latency in B cells. However, although these viruses share genomic similarities there are diVerences that reflect development along distinct evolutionary pathways. For example, the KSHV genome encodes several cellular homologues not present in EBV. These include, among others, viral interleukin 6 (vIL-6) and viral cyclin D (v-cyclin D) genes. However, LMP1 is able to induce the expression of both cellular IL-6 and cellular cyclin D genes. 4 Therefore, both viruses have evolved diVerent means (expression of viral homologues in the case of KSHV versus induction of cellular genes by EBV) to produce the same functional endpoints. This tells us that such gene functions are likely to be important for ã-herpesvirus physiology in general. In fact, much more is now known about the functions of some of the virus genes expressed by EBV during virus latency (see Young et al, this issue). Much of the study of latent gene function has focused on EBV infection of B cells because this is the cell type most easily infectable in vitro and also the most likely candidate for the natural site of virus persistence in the normal carrier. Of the latent genes, LMP1 has been the focus of particularly intense investigation. LMP1 is a transmembrane protein that has been shown to be transforming in several diVerent situations and, together with several other latent genes, has been shown to be essential for EBV induced immortalisation of B cells. LMP1 has little sequence homology with any known mammalian proteins, although it retains the ability to initiate signalling along several pathways, which include the nuclear factor-êB (NF-êB) and JNK (c-Jun NH2-terminal kinase) pathways—a function reminiscent of other transmembrane proteins of the tumour necrosis factor receptor (TNFR) family. 7 However, unlike normal TNFRs, which require ligand binding for their activation, LMP1 is constitutively activated in infected cells. Blocking the important signalling activities of LMP1 abrogates transformation and testifies to the importance of such events in the transformation process. Like LMP1, EBNA2 is also essential for B cell transformation. This was demonstrated several years ago in experiments showing that EBV strains deleted for the EBNA2 coding regions were non-transforming and that restoration of the EBNA2 sequence to these strains restored their transformation ability. More recent studies of EBNA2 function have provided important insights into its function during infection. EBNA2 mimics the activated J Clin Pathol: Mol Pathol 2000;53:219–221 219