Epstein-Barr Virus infection results in growth transformation of human B lymphocytes. Despite the persistence of the complete virus genome in infected cells there is usually no virus replication and the infection is said to be latent. However, at least four EBV genes are expressed in """"""""latently"""""""" infected growth transformed lymphocytes. The genes and gene products have been largely defined. One of these genes is transcribed from right to left from the EBV genome and encodes a membrane protein (LMP). LMP appears to aggregate in patches in the plasma membrane. The LMP gene causes rodent cells to partially resist the growth inhibiting effects of medium containing low serum. In Rat-1, but not in NIH3T3 cells, expression of the gene results in loss of contact inhibition, anchorage independence and enhanced tumorigenicity. The other three genes are transcribed from left to right from the EBV genome. Their transcription is probably coordinately regulated from the same start site. The relative rate of synthesis of the three mRNAs may be regulated by differential rates of polyadenylation. The three mRNAs encode three distinctly different nuclear proteins (EBNA1, EBNA2, or EBNA3). A fourth nuclear protein (designated LP) is encoded by a leader probably common to the nuclear protein mRNAs. EBNA1 binds to a domain 7kb upstream from the EBNA transcriptional start site. EBNA1 binding to this site is necessary for EBV DNA episome maintenance and probably enhances transcription from neighboring promotors. EBNA2 introduced into rodent cells reduces their serum requirement. EBNA2 may be an immortalizing gene. EBNA3 is one of three related EBV genes whose functions have not been explored. The objectives of this proposal are to further define (1) the role of these EBV genes in cell immortalization and growth transformation using recombinant expression vectors, (2) the molecular basis for the effects of these genes on cell growth, (3) the basis for the immune response to latently infected cells and (4) the role of the viral glycoproteins in earliest stages of viral infection and in the immune response to primary EBV Infection.
Showing the most recent 10 out of 19 publications
