A nucleic acid is provided which encodes a human TRIM-cyclophilin A fusion sequence encoding a human TRIM-CypA fusion protein which is active as an anti-viral agent, and in particular, as an anti-HIV-1 agent. Also provided is a nucleic acid encoding a polypeptide having both TRIM activity and cyclophilin activity. Also provided is an isolated polynucleotide encoding a human TRIM-CypA fusion protein, or variants thereof retaining the TRIM and cyclophilin A activities. Also provided are compositions thereof, antibodies that specifically bind thereto, and vectors and host cells comprising the nucleic acid or polypeptide. In addition, methods are provided for treating or preventing viral infection, or reducing viral load in a subject comprising administering the nucleic acid, polypeptide, vector, or composition to the subject in an amount effective to treat or prevent the viral infection. In some embodiments, the viral infection is HIV-I infection, hepatitis C infection, pox virus infection, vaccinia virus infection, or HTLV infection.