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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.

ORGANISM(S): Cytomegalovirus Humanbeta5

SUBMITTER: Chloe Cavanaugh

PROVIDER: PXD058198 | panorama | Sat Feb 01 00:00:00 GMT 2025

REPOSITORIES: PanoramaPublic

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Project description:Human cytomegalovirus (HCMV) replication requires host metabolism. Infection alters the activity in multiple metabolic pathways, including increasing fatty acid elongation and lipid synthesis. The virus-host interactions regulating the metabolic changes associated with replication are essential to infection. While multiple host factors, including kinases and transcription factors, have been identified to be important to metabolic changes that occurr following HCMV infection, little is known about the viral factors required to alter metabolism. The HCMV UL37x1 protein (pUL37x1) localizes to the mitochondria and ER and controls Ca2+ flux from the ER to the cytosol which may influence metabolism. In this study, we tested the hypothesis that pUL37x1 is important to the metabolic remodeling that is necessary for HCMV replication by using a combination of metabolomics, lipidomics, and metabolic tracers to measure fatty acid elongation. We observed that fibroblast cells infected with wild-type (WT) HCMV had similar levels of metabolites as those infected with a mutant virus lacking the UL37x1 gene, subUL37x1. However, we found that subUL37x1-infected cells had reduced levels of two host proteins that were previously demonstrated to be important for lipid metabolism during HCMV infection—fatty acid elongase 7 (ELOVL7) and ER-stress related kinase PERK—relative to WT-infected cells. Moreover, we observed that HCMV infection results in an increase in phospholipids with very long-chain fatty acid tails (PL-VLCFAs) that contain 26 or more carbons in one of their two tails. The levels of many PL-VLCFAs were lower in subUL37x1-infected cells compared to WT-infected cells. We also show that uninfected cells expressing a high-level of pUL37x1 have a greater amount of lipids relative to control cells. Overall, we conclude that although pUL37x1 is not necessary for network-wide metabolic changes occurring during infection, it is important to the remodeling of lipid metabolic pathways during HCMV infection.

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Effect of Host Telomerase Inhibition on Human Cytomegalovirus

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