Investigating the Role of Host Cell Telomerase in the Human Cytomegalovirus Life Cycle

Abstract

Human cytomegalovirus (HCMV) is a common beta herpesvirus that causes lifelong infection. Although often asymptomatic in immunocompetent hosts, active HCMV infection in immunocompromised individuals and developing fetuses can lead to severe morbidity, and there is no cure or vaccination for HCMV. A previous study by Strååt et al. (2009) found that HCMV upregulates the activity of telomerase, the reverse transcriptase responsible for maintaining telomeres, the protective DNA sequences located at the ends of chromosomes. Telomerase is implicated in stress, aging, and cancer, and preliminary data suggests telomerase inhibition reduces HCMV viral replication (Cavanaugh and Notterman, unpublished results). The overarching goal of this project is to examine the relationship between telomerase activity and HCMV. By inhibiting telomerase at strategic time points within the viral life cycle, we demonstrated that telomerase inhibition at the immediate early stage results in lowest levels of viral titer and telomerase activity, suggesting that this stage is important to HCMV-mediated telomerase upregulation. Our findings further suggest that hTERT, which codes for the catalytic portion of telomerase, is not increased as a secondary effect of low viral titer. Additionally, we discovered a novel mode of de-repression of hTERC, which codes for the RNA subunit of telomerase. Lastly, we found that telomerase inhibition results in changes in viral protein levels but not viral mRNA expression, suggesting that telomerase plays a role in viral translation. Taken together, these results begin to elucidate a mechanism by which HCMV upregulates telomerase activity and may provide insight into future therapeutic developments.