Immortalizing genes of Epstein-Barr virus.
EBV immortalizes human B lymphocytes efficiently. Ten of its approximately 100 genes are expressed in these proliferating lymphoblasts and are candidates for mediating the changes central to the immortalization of the cell. Enough has been learned now about three of these viral genes to indicate that they are likely to be required for immortalization. As more is learned, additional genes of EBV will probably be found to support the process of immortalization of the host cell. EBNA-2 has been shown genetically to be required for EBV to immortalize an infected B lymphocyte. The biochemical activities of EBNA-2 that constitute this requirement have not been identified. Many experiments indicate that EBNA-2 affects the accumulation of specific viral and cellular RNAs. These effects, however, can be detected only in certain EBV-negative B-lymphoblastoid cells. It is, therefore, not clear that the known effects of EBNA-2 adequately explain its ubiquitous requirement in the immortalization of primary human B lymphocytes. LMP is likely to be required for immortalization because it can affect the growth properties of established human lymphoid and epithelial cells and can transform at least two established rodent cells to proliferate in an anchorage-independent manner. The structure of this viral protein, its position in the plasma membrane, many of its biochemical properties, as well as studies of its mutant derivatives are consistent with its acting as a growth factor receptor or affecting the activity of such a receptor. However, no biochemical activity has been assigned directly to LMP, and both its mechanism of action and its possible contribution to immortalization by EBV remain enigmatic. EBNA-1 presumably is required for EBV to immortalize a B lymphocyte because it is essential for the initiation of plasmid DNA replication by EBV. Circumstantial observations indicate also that EBNA-1 is probably necessary for sustaining viral DNA replication in the proliferating cell population. EBNA-1 may well affect the regulation of transcription of viral genes that themselves are required for immortalization. These roles of EBNA-1 are performed in part by its site-specific binding to the elements of oriP required in cis for the replication of EBV plasmid DNAs. It is probable that EBNA-1 also binds both to a set of cellular proteins that function in transcription and to a nonidentical set of cellular proteins that function in replication. EBV effects a fascinating phenotypic change in B lymphocytes it infects. It does so by using several viral genes that alter the physiology of the cell by different means.(ABSTRACT TRUNCATED AT 400 WORDS)
Middleton
T
T
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706.
Gahn
T A
TA
Martin
J M
JM
Sugden
B
B
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics; D001483:Base Sequence; D002472:Cell Transformation, Viral / Q000235:genetics*; D004279:DNA, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D014763:Viral Matrix Proteins
D000956:Antigens, Viral; D004279:DNA, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D014763:Viral Matrix Proteins