Disclosed herein are several apoplipoprotein E (ApoE) polypeptides, and nucleic acids encoding these polypeptides, that can be used to treat or prevent a hepatitis infection in a subject, such as a hepatitis C virus infection. These ApoE polypeptides can inhibit the entry of hepatitis C virus into cells, and inhibit viral replication. Nucleic acids encoding these polypeptides are also disclosed, as well as methods for their preparation.