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Synthetic peptide vaccines containing a single Th cell epitope identified in the gp70 envelope glycoprotein of Friend murine leukemia helper virus induced potent protective immunity against Friend virus infection. H-2a/b mice immunized by a single s.c. injection of the CFA emulsion containing a peptide that represented the N-terminal gp70 epitope recovered slowly from initial development of splenomegaly, and most did not develop late leukemia, whereas most of the control mice given an injection of CFA alone showed sustained leukemic splenomegaly after the challenge with Friend virus. The mice of the same genetic background immunized with the C-terminal Th cell epitope by a single injection of a separate synthetic peptide eliminated virus-producing cells from the spleen within 12 days after inoculation of Friend virus complex, and did not develop early splenomegaly or polycythemia. H-2a/a mice were not protected by immunization with either one of the two synthetic peptides. Earlier production and more rapid class switching of virus-neutralizing Abs were observed in H-2a/b mice immunized with the peptide vaccines after the challenge with Friend virus, compared with the responses of the control mice. Detailed kinetic and immunohistopathologic analyses suggested that Th cells might be directly involved in the growth inhibition and elimination of virus-infected erythroid precursor cells.