hTERT inhibits the Epstein-Barr virus lytic cycle and promotes the proliferation of primary B lymphocytes: implications for EBV-driven lymphomagenesis

Abstract

Transformation of primary B lymphocytes by Epstein-Barr Virus (EBV) requires the establishment of a latent infection, the expression of several latent viral proteins and a sustained telomerase activity. We investigated the interplay between the activation of human telomerase reverse transcriptase (hTERT), the catalytic rate-limiting component of the telomerase complex, and the expression of latent/lytic EBV genes during the establishment of a stably latent EBV infection of normal B lymphocytes. Cell cultures at early passages after EBV infection greatly differed in their timing of hTERT expression and telomerase activation. Induction of hTERT was dependent on the balance between latent and lytic EBV gene expression, being positively associated with a high ratio of latent/lytic isoforms of latent membrane protein 1, and negatively associated with the expression of BZLF1 gene, the main activator of the viral lytic cycle. In turn, hTERT expression was followed by a decrease in EBV lytic gene expression and virus production. Ectopic expression of hTERT in BZLF1-positive B cell cultures resulted in BZLF1 down-regulation, increased resistance to lytic cycle induction, and enhanced in vitro growth properties, whereas hTERT inhibition by siRNA triggered the activation of the EBV lytic cycle. These findings indicate that hTERT contributes by multiple mechanisms to the EBV-driven transformation of B lymphocytes and suggest that hTERT may constitute a therapeutic target for EBV-associated B cell lymphomas.