p53 inhibition by the LANA protein of KSHV protects against cell death

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B- cen lymphoproliferative diseases(1-3) Most cells in lesions derived from th ese malignancies are latently infected, and different viral gene products h ave been identified in association with lytic or latent infection by KSHV4, 5. The latency-associated nuclear antigen (LANA), encoded by open reading f rame 73 of the KSHV genome, is a highly immunogenic protein that is express ed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas(6,7). Antibodies to LAN A can be detected in a high percentage of HIV-infected individuals who subs equently develop KS8,9, although its role in disease pathogenesis is not co mpletely understood. p53 is a potent transcriptional regulator of cell grow th whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis(10,11), an d several viral oncoproteins interact with p53 and modulate its biological activity(12-13). Here we show that LANA interacts with the tumour suppresso r protein p53 and represses its transcriptional activity. This viral gene p roduct further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through i ts ability to promote cell survival by altering p53 function.