Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Author:

Sun Xiaoping1,Bristol Jillian A.1,Iwahori Satoko12,Hagemeier Stacy R.1,Meng Qiao1,Barlow Elizabeth A.1,Fingeroth Joyce D.3,Tarakanova Vera L.4,Kalejta Robert F.12,Kenney Shannon C.15

Affiliation:

1. Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

2. Institute for Molecular Virology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

3. Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

4. Department of Microbiology and Molecular Genetics, Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

5. Department of Medicine, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

Abstract

ABSTRACT All eight human herpesviruses have a conserved herpesvirus protein kinase (CHPK) that is important for the lytic phase of the viral life cycle. In this study, we show that heat shock protein 90 (Hsp90) interacts directly with each of the eight CHPKs, and we demonstrate that an Hsp90 inhibitor drug, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreases expression of all eight CHPKs in transfected HeLa cells. 17-DMAG also decreases expression the of the endogenous Epstein-Barr virus protein kinase (EBV PK, encoded by the BGLF4 gene) in lytically infected EBV-positive cells and inhibits phosphorylation of several different known EBV PK target proteins. Furthermore, 17-DMAG treatment abrogates expression of the human cytomegalovirus (HCMV) kinase UL97 in HCMV-infected human fibroblasts. Importantly, 17-DMAG treatment decreased the EBV titer approximately 100-fold in lytically infected AGS-Akata cells without causing significant cellular toxicity during the same time frame. Increased EBV PK expression in 17-DMAG-treated AGS-Akata cells did not restore EBV titers, suggesting that 17-DMAG simultaneously targets multiple viral and/or cellular proteins required for efficient viral replication. These results suggest that Hsp90 inhibitors, including 17-DMAG, may be a promising group of drugs that could have profound antiviral effects on herpesviruses.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

Reference103 articles.

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