title: High Glucose Induces Reactivation of Latent Kaposi's Sarcoma-Associated Herpesvirus.
abstract: A high prevalence of Kaposi's sarcoma (KS) is seen in diabetic patients. It is unknown if the physiological conditions of diabetes contribute to KS development. We found elevated levels of viral lytic gene expression when Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells were cultured in high-glucose medium. To demonstrate the association between high glucose levels and KSHV replication, we xenografted telomerase-immortalized human umbilical vein endothelial cells that are infected with KSHV (TIVE-KSHV cells) into hyperglycemic and normal nude mice. The injected cells expressed significantly higher levels of KSHV lytic genes in hyperglycemic mice than in normal mice. We further demonstrated that high glucose levels induced the production of hydrogen peroxide (H2O2), which downregulated silent information regulator 1 (SIRT1), a class III histone deacetylase (HDAC), resulting in the epigenetic transactivation of KSHV lytic genes. These results suggest that high blood glucose levels in diabetic patients contribute to the development of KS by promoting KSHV lytic replication and infection.IMPORTANCEMultiple epidemiological studies have reported a higher prevalence of classic KS in diabetic patients. By using bothin vitroandin vivomodels, we demonstrated an association between high glucose levels and KSHV lytic replication. High glucose levels induce oxidative stress and the production of H2O2, which mediates the reactivation of latent KSHV through multiple mechanisms. Our results provide the first experimental evidence and mechanistic support for the association of classic KS with diabetes.
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA fxy63@case.edu shoujiag@usc.edu.|Department of Pediatrics, Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Ye
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Pediatrics, Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Jones
authors.affiliation: Department of Pediatrics, Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Kuhne
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wood
authors.affiliation: Department of Pediatrics, Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas, USA fxy63@case.edu shoujiag@usc.edu.|Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao