Effect of host telomerase inhibition on human cytomegalovirus.

Abstract

Treatment options remain limited for human cytomegalovirus (HCMV). Host telomerase has been implicated in the pathogenesis and oncogenesis of multiple herpesviruses, most recently including HCMV. In this study, we investigated the effect of telomerase inhibition on HCMV replication, as well as the mechanism of the interaction between HCMV and host telomerase in vitro. We found that lytic HCMV infection increases host telomerase activity, at least in part, through modulation of hTERT expression during earlier phases of the HCMV replication cycle. We found telomerase inhibition strongly reduced viral titer for two HCMV strains in a dose-specific manner. Both post-translational pharmaceutical telomerase inhibition and siRNA-mediated knockdown of hTERT reduce HCMV yield. Telomerase inhibition results in both reduction of viral gene and protein expression across the HCMV replication cycle, and suppressed viral genome replication and viral infectivity, suggesting interference with at least early steps of the HCMV viral life cycle. Altogether, our findings indicate telomerase plays an important, perhaps non-canonical role in lytic HCMV infection which includes the support of viral replication and infectivity.

Importance: Human cytomegalovirus (HCMV) seroprevalence and morbidity in immunocompromised patients and neonates infected in utero remain high globally. Host telomerase has been implicated in the success of multiple infection-induced pathologies, including the success of both lytic infection and oncogenesis in certain herpesviruses. The results of this study suggest a similar biologically important role for host telomerase in lytic HCMV infection. Furthermore, these results may provide the potential for a novel, adjunctive anti-viral treatment for HCMV infection as well as insight into the viral products likely to be involved with HCMV regulation of telomerase.