Evidence as a HIV-1 self-defense vaccine of cyclic chimeric dodecapeptide warped from undecapeptidyl arch of extracellular loop 2 in both CCR5 and CXCR4.
Novel conformation-specific antibodies were raised against a cyclic chimeric dodecapeptidyl multiple antigen peptide (cCD-MAP) constructed with a spacer-armed Gly-Asp dipeptide and two pentapeptides (S(169)-Q(170)-K(171)-E(172)-G(173) of CCR5 and E(179)-A(180)-D(181)-D(182)-R(183) of CXCR4) which are components of the undecapeptidyl arch (UPA: from R(168) to C(178) in CCR5, from N(176) to C(186) in CXCR4) of extracellular loop 2 (ECL2) in chemokine receptors (CCR5 and CXCR4). Of the antibodies raised, one monoclonal antibody, CPMAb-I (IgMkappa), reacted with cCD-MAP, but not with the linear chimeric dodecapeptide-MAP. The antibody reacted with the cells separately expressing CCR5 or CXCR4, but not with those not expressing the coreceptors. Moreover, the antibody markedly suppressed infection by X4, R5, or R5X4 virus in a dose-dependent manner in a new phenotypic assay for drug susceptibility of HIV-1 using CCR5-expressing Hela/CD4(+) cell clone 1-10 (MAGIC-5). Moreover, CPMAb-I interfered with LAV-1(BRU) infection (m.o.i. = 0.01) of Molt4#8 cells cocultured with CPMAb-I-producing hybridoma in the transwell, and significantly interfered with neither chemotaxis nor calcium influx induced with stromal cell-derived factor 1 alpha (SDF-1alpha). Thus, the antibody raised against the cCD-MAP provides powerful protection or defense against HIV-1 infection. We therefore propose the cCD-MAP or its derivative immunogen as a novel candidate for an HIV-1 coreceptor-based self-defense vaccine.
Misumi
S
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, 862-0973, Japan.
Takamune
N
N
Ido
Y
Y
Hayashi
S
S
Endo
M
M
Mukai
R
R
Tachibana
K
K
Umeda
M
M
Shoji
S
S
D016915:AIDS Vaccines / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D000918:Antibody Specificity / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D001681:Biological Assay; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000737:chemistry / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D018925:Chemokines; D000939:Epitopes; D010455:Peptides; D010456:Peptides, Cyclic; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014614:Vaccines, Synthetic; C434047:cyclic chimeric dodecapeptidyl multiple antigen peptide