Viruses persistently threaten human health. Available antivirals do not fully eliminate infections. Development of drugs that enhance innate immunity could serve as broad-spectrum antivirals evading future pandemics. Similarly, cancer is a major health concern and leading cause of death. Conventional anticancer treatments have low specificity and high toxicity. Innovative therapies, such as the use of cancer-killing (oncolytic) viruses are worth exploring. Virotherapy, however, poses a threat of uncontrolled systemic infection and before further development, meticulous control of viral replication must be established. Statins, best known as cholesterol-lowering drugs, exert effects that inhibit seemingly unrelated viruses such as HIV, polio, and vesicular stomatitis virus (VSV). The latest is a well characterized oncolytic virus that disrupts cellular gene expression by blocking mRNA export from the nucleus. Aggressive cancers are vulnerable to VSV because they lack pathways for antiviral response. Statins modulate VSV in a biphasic pattern (unpublished results). At low concentrations, statins enhance replication, potentiating cancer apoptosis. At higher concentrations, statins up-regulate the expression of antiviral proteins and inhibit viral replication. The mechanisms behind such drug actions on modulation of gene expression (both viral and cellular) remain unclear. At a molecular level, methylation of DNA plays important roles in regulating overall gene expression. To determine whether statins alter genomic methylation of DNA as a mechanism for modulation of gene expression, we propose to (Specific Aim I) study methylation patterns by comparing statin-treated, infected and non-treated cells, followed by (Specific Aim II) correlation of such changes in methylation with statins' modulation of gene expression. Our innovative approach utilizes state-of-the art technology for elucidation of important pathways and interactions between host and virus. By examining epigenetic control of gene expression during oncolytic viral infection, we link the fields of genomics, virology, oncology and immunology, proportionating new avenues for design of effective antiviral and anticancer therapy.