Statins Attenuate the Replication of Vesicular Stomatitis Virus and Modulate Viral Oncolysis

Objective. To study statins as antiviral agent in viral oncolytic treatment. Background. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, reduce the levels of LDL-cholesterol. Statins have other pleotropic properties, such as anti-inflammatory, antibacterial and antiviral. Statins may affect the infectivity and proliferation of microorganisms, therefore serving as potential prophylaxis for infectious diseases. The Vesicular Stomatitis Virus (VSV) is an oncolytic virus that differentially kills cancer cells. Protecting normal cells against VSV infection is crucial for successful therapy. Methods. HeLa cells were cultured in vitro. Cells were treated with Simvastatin, Lovastatin, Pravastatin or Methyl-b-cyclodextrin (MBCD) for time-points ranging from 2 to 24 hrs. Infections with VSV-GFP followed. Viral proteins were analyzed by WB. Cell viability was determined by standard MTT assay. Imaging of cells was obtained with a Zeiss LSM510 confocal microscope. Results. Cells treated with low concentration of Simvastatin (0.125uM) showed significant increase in viral proteins ranging from 50% to 100% relative to control. Higher concentrations of Simvastatin (from 0.25uM to 2uM) showed a dose-dependent decrease in total viral protein. Treatment with increasing concentrations of MBCD showed increased expression of viral proteins. Viral titer profiles correlated with the attenuation observed by WBs. Conclusion. Our results show that statins attenuate VSV infection at the level of viral replication. These observations are independent of cholesterol content, which indicate that statins are acting on genes that affect innate immunity. Our data support the use of statins as neoadjuvant and/or as attenuator of VSV oncolytic therapy. Grant. NSU Health Professions Division Award 2008-09.