Mechanism and Therapeutic Implication of Host Telomerase Modulation by Human Cytomegalovirus

Abstract

Treatment options remain limited for human cytomegalovirus (HCMV), a double-stranded DNA herpesvirus with acute and chronic pathogenic as well as potential oncomodulatory effects 1–3. While several anti-viral drugs attenuate active infection, efficacy is limited 4, viral resistance is significant, and there is no existing method to eradicate the virus from latent infection of mononuclear cells. This means that once infected, humans are infected for life, and at risk of recrudescence as their immune competence fluctuates. HCMV seroprevalence and morbidity in immunocompromised patients and neonates infected in utero remains high in both developed and developing nations 5. Therefore, this virus remains a critical target for permanent effective antiviral therapy 5,6. The reverse transcriptase, telomerase, is a key component of the eukaryotic system to manage the end replication issue and to protect the integrity of chromosome ends. While telomerase has been extensively characterized in diverse systems 7,8 and links to stress, aging, and cancer are under active exploration 9–11, recently host cell telomerase has been shown to be sharply upregulated in response to infection by HCMV laboratory and clinical strains 12. After confirming these initial observations, we sought to investigate the therapeutic implications of telomerase inhibition on HCMV as well as the mechanism of the interaction between HCMV and host telomerase in vitro. Here, we describe the effects of telomerase inhibition, both by post-translational, pharmaceutical inhibition as well as siRNA-mediated genetic inhibition, on the HCMV replication cycle. Additionally, we examine the potential mechanisms by which telomerase benefits HCMV. Latent HCMV infection is lifelong and currently ineradicable. Understanding the biological mechanism and clinical significance of the interaction of telomerase and HCMV is important, and these insights may be harnessed to develop a novel therapy for HCMV infection. Establishing the relationship between telomerase and HCMV may further provide insights to HCMV biology and expand the knowledge of herpesvirus interactions with telomerase and telomeres.