Human Cytomegalovirus Activates Telomerase Through a Mechanism Mediated by Immediate Early or Delayed Early Viral Gene Products

Abstract

Telomeres are conserved, tandem repeats of DNA that cap the ends of chromosomes and provide chromosome stability by preventing fusion of chromosomal ends and loss of coding DNA. Telomeres are maintained by the ribonucleoprotein reverse transcriptase telomerase, which is regulated by a variety of proteins and RNAs. Human cytomegalovirus (HCMV) is a beta-herpes virus that infects a large proportion of the population world-wide. While mostly asymptomatic in immunocompetent patients, active infection can have detrimental effects on the immunocompromised; in addition, the virus is one of the leading causes of congenital neurological defects in infants. Moreover, HCMV has been implicated as a possible oncogenic agent and tumors of many kinds have been found to express viral products while adjacent areas do not. In this study, we wanted to investigate how acute HCMV infection changed telomerase activity and telomere length. To do this, we used a non-radioactive telomerase repeat amplification protocol to quantify the relative telomerase activity in cells infected with HCMV. We also used a quantitative real time polymerase chain reaction to measure the absolute telomere length. We discovered infection with HCMV causes an increase in telomerase activity of infected fibroblast cells, but no changes were seen in telomere length during acute infection. We showed that major immediate early proteins IE-72 and IE-86, as well as viral late genes, are not sufficient to cause this increase. We also demonstrated that the increase in telomerase activity is not likely to be a host cell response to the invasion of the HCMV viral particle. In addition, we observed that infection with either an active or inactive virus results in possible changes in the RNA expression of telomerase- and telomere associated genes hTERT, POT1, DKC1, TRF2, and NHP2. Future studies should continue to try to identify the immediate early or delayed early gene responsible for the increase in telomerase seen during infection. By developing a model by which HCMV mediates an induction in telomerase activity, it may become possible to stop the growth of HCMV-positive tumors by blocking the effect of viral products on telomerase.