Abstract: Methods and compositions treat a viral infection use a nuclease and an inhibitor that prevents DNA repair, such as a CRISPR-associated nuclease and a small molecule that inhibits an enzyme of a repair pathway. Under guidance of a targeting sequence, the nuclease cuts viral nucleic acid without cutting the patient's genome. The cut ends of the viral nucleic acid are not repaired because the inhibitor prevents a repair mechanism.

Abstract: Compositions and methods are disclosed for reducing toxicity and immunogenicity of nucleases, especially when in use for cutting viral nucleic acids in host cells. Different nucleases that cut the same target are delivered at different times to avoid an immune response that interferes with a therapeutic effect of the nucleases.