Epstein-Barr virus provides a new paradigm: a requirement for the immediate inhibition of apoptosis.
DNA viruses such as herpesviruses are known to encode homologs of cellular antiapoptotic viral Bcl-2 proteins (vBcl-2s), which protect the virus from apoptosis in its host cell during virus synthesis. Epstein-Barr virus (EBV), a human tumor virus and a prominent member of gamma-herpesviruses, infects primary resting B lymphocytes to establish a latent infection and yield proliferating, growth-transformed B cells in vitro. In these cells, 11 viral genes that contribute to cellular transformation are consistently expressed. EBV also encodes two vBcl-2 genes whose roles are unclear. Here we show that the genetic inactivation of both vBcl-2 genes disabled EBV's ability to transform primary resting B lymphocytes. Primary B cells infected with a vBcl-2-negative virus did not enter the cell cycle and died of immediate apoptosis. Apoptosis was abrogated in infected cells in which vBcl-2 genes were maximally expressed within the first 24 h postinfection. During latent infection, however, the expression of vBcl-2 genes became undetectable. Thus, both vBcl-2 homologs are essential for initial cellular transformation but become dispensable once a latent infection is established. Because long-lived, latently infected memory B cells and EBV-associated B-cell lymphomas are derived from EBV-infected proapoptotic germinal center B cells, we conclude that vBcl-2 genes are essential for the initial evasion of apoptosis in cells in vivo in which the virus establishes a latent infection or causes cellular transformation or both.
Altmann
Markus
M
Department of Gene Vectors, GSF-National Research Center for Environment and Health, München, Germany.
Hammerschmidt
Wolfgang
W
D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics
C505906:BALF1 protein, Epstein-Barr virus; C083278:BHRF1 protein, Human herpesvirus 4; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014764:Viral Proteins