Immunogenicity of and apoptosis modulation by Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1) : Implications for nasopharyngeal carcinoma

Sammanfattning: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus which infects more than 90% of individuals in the population, and has been shown to be associated with a variety of human tumors. The viral genome encodes a number of transforming proteins which enable the virus to efficiently immortalize B lymphocyte and also transform cells of other types. Among the viral genetic products, a membrane integral latent infection protein, latent membrane protein-1 (LMP1) is of particular interest, since it possesses in vitro transforming ability and is expressed in more than two-thirds of EBV positive nasopharyngeal carcinoma (NPC), which arises in immunocompetent hosts. Because of the distinctive geographic distribution and ethnic prevalence of NPC, strain variations of EBV carrying mutations in LMP1 have been investigated to correlate its presence in malignancy. Enhanced ability in transducing cellular signals as well as altered immunogenicity have been identified in LMP1 variant genes isolated from NPC specimens originating from the endemic regions. In the present study, a comparison of immunogenicity as related to the status of LMP1 expression in NPC biopsies has been made. Our data (Paper I) show that LMP1 strains from LMP1-positive NPC contain more sequence variations than those from LMP1-negative NPC, and are less immunogenic. These results suggest a viral escape from host immune surveillance through genetic mutation in NPC. Modulation of host cell apoptosis is a strategy utilized by viruses to escape host immunity. LMP1 has been observed to reduce apoptosis in B and T cells, but its effect on apoptosis in epithelial cells remains obscure. We provide evidence herein (Paper II) for a stimulus-dependent apoptosis modulation by LMP1 in HeLa cells with tetracycline-regulated LMP1 expression; hence, LMP1 reduces tumor necrosis factor (TNF)-