Suppression of multiclade R5 and X4 human immunodeficiency virus type-1 infections by a coreceptor-based anti-HIV strategy.
A cyclic chimeric dodecapeptide (cCD) mimicking the conformation-specific domains of CCR5 and CXCR4 was prepared in which Gly-Asp links the amino and carboxyl termini of two combined pentapeptides (S169-G173 of CCR5; E179-R183 of CXCR4) derived from human immunodeficiency virus type-1 (HIV-1) coreceptors. The immunization of Balb/c mice with cCD conjugated with a multiple-antigen peptide (cCD-MAP) induced seven cCD-specific monoclonal antibodies (mAbs, CPMAb-I to -VII) that reacted with native CCR5 and CXCR4. Among the tested mAbs, CPMAb-I and -II potently inhibited the infection of both the R5 and X4 laboratory strains. CPMAb-III and -VI were effective against only R5 laboratory strains, and also against some X4 and R5 primary isolates. CPMAb-IV and -V had potent antiviral activities against the R5 and X4 primary isolates. In particular, CPMAb-VII was protective against not only R5 and X4 laboratory strains, but also most of the R5 and X4 primary isolates. Moreover, cCD-MAP immunization also induced antibodies that were effective against R5 and X4 multiclade HIV-1 isolates in vitro in two of three cynomolgus monkeys. Taken together, the results suggest that cCD-MAP is a candidate multiclade immunogen that can be used to block multiclade R5 and X4 HIV-1 infections.
Nakayama
Daisuke
D
Department of Pharmaceutical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973.
Misumi
Shogo
S
Mukai
Ryouzaburo
R
Tachibana
Kuniomi
K
Umeda
Mamoru
M
Shibata
Hideaki
H
Takamune
Nobutoki
N
Shoji
Shozo
S
D016915:AIDS Vaccines; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018450:Disease Progression; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D010456:Peptides, Cyclic; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000737:chemistry / Q000276:immunology; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000276:immunology
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D010455:Peptides; D010456:Peptides, Cyclic; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C434047:cyclic chimeric dodecapeptidyl multiple antigen peptide