title: Sequential immunization with V3 peptides from primary human immunodeficiency virus type 1 produces cross-neutralizing antibodies against primary isolates with a matching narrow-neutralization sequence motif.
abstract: An antibody response capable of neutralizing not only homologous but also heterologous forms of the CXCR4-tropic human immunodeficiency virus type 1 (HIV-1) MNp and CCR5-tropic primary isolate HIV-1 JR-CSF was achieved through sequential immunization with a combination of synthetic peptides representing HIV-1 Env V3 sequences from field and laboratory HIV-1 clade B isolates. In contrast, repeated immunization with a single V3 peptide generated antibodies that neutralized only type-specific laboratory-adapted homologous viruses. To determine whether the cross-neutralization response could be attributed to a cross-reactive antibody in the immunized animals, we isolated a monoclonal antibody, C25, which neutralized the heterologous primary viruses of HIV-1 clade B. Furthermore, we generated a humanized monoclonal antibody, KD-247, by transferring the genes of the complementary determining region of C25 into genes of the human V region of the antibody. KD-247 bound with high affinity to the "PGR" motif within the HIV-1 Env V3 tip region, and, among the established reference antibodies, it most effectively neutralized primary HIV-1 field isolates possessing the matching neutralization sequence motif, suggesting its promise for clinical applications involving passive immunizations. These results demonstrate that sequential immunization with B-cell epitope peptides may contribute to a humoral immune-based HIV vaccine strategy. Indeed, they help lay the groundwork for the development of HIV-1 vaccine strategies that use sequential immunization with biologically relevant peptides to overcome difficulties associated with otherwise poorly immunogenic epitopes.
authors.affiliation: AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Eda
authors.forename: Mari
authors.initials: M
authors.lastname: Takizawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Murakami
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Maeda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kimachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yonemura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Shiosaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Higuchi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Makizumi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakashima
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Osatomi
authors.forename: Sachio
authors.initials: S
authors.lastname: Tokiyoshi
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Honda
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D003429:Cross Reactions; D000939:Epitopes; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology* / Q000302:isolation & purification; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*
chemical_list: D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments