The invention features methods and compositions for use in a screening assay to identify agents having antiviral activity against a DNA virus by assessing the effect of a candidate agent upon alternative splicing of MxA, or by assessing the effect of a candidate agent on production of a variant form of MxA protein. The invention also provides methods for enhancing resistance of cells to infection by a DNA virus by providing for elevated MxA and/or by providing for reduced production of variant MxA protein.