A novel cyclic peptide immunization strategy for preventing HIV-1/AIDS infection and progression.
A novel synthetic peptide immunogen targeting the human immunodeficiency virus type-1 (HIV-1) coreceptor CXCR4 was evaluated for its capacity to induce CXCR4-specific antibodies with anti-HIV-1 activity in BALB/c mice and cynomolgus monkeys. A cyclic closed-chain dodecapeptide mimicking the conformation-specific domain of CXCR4 (cDDX4) was prepared in which Gly-Asp, as the dipeptide forming a spacer arm, links the amino and carboxyl termini of the decapeptidyl linear chain (linear DDX4, Asn176 to Ile185) derived from the undecapeptidyl arch (UPA; Asn176 to Cys186) of extracellular loop 2 (ECL-2) in CXCR4. Immunization of BALB/c mice with cDDX4 conjugated with a multiple-antigen peptide (cDDX4-MAP) induced conformational epitope-specific antibodies, and monoclonal antibody IA2-F9 reacted with cDDX4, but not with linear DDX4, as determined by real-time biomolecular interaction analysis using surface plasmon resonance. The antibody also reacted with cells expressing CXCR4 but not with cells expressing the other HIV coreceptor, CCR5. Furthermore, the antibody inhibited the replication of HIV-1 X4 virus (using CXCR4), as shown by an infection assay using both MAGIC-5 cells and MT4 cells, but not that of HIV-1 R5 virus (using CCR5). The antibody weakly interfered with chemotaxis induced by stromal cell-derived factor-1 alpha in THP-1 cells or moderately inhibited the chemotaxis of Molt4#8 cells under the same conditions. In addition, immunization of cynomolgus monkeys also induced cDDX4-specific antibodies with anti-HIV activity. Taken together, these results indicate that cDDX4 conjugated with a multi-antigen peptide induces the conformational epitope-specific antibodies to the undecapeptidyl arch of CXCR4 may be a novel candidate immunogen for preventing disease progression in HIV-1-infected individuals.
Misumi
Shogo
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Kumamoto, 862-0973, Japan.
Endo
Masafumi
M
Mukai
Ryouzaburou
R
Tachibana
Kuniomi
K
Umeda
Mamoru
M
Honda
Tetsuro
T
Takamune
Nobutoki
N
Shoji
Shozo
S
D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D015497:HIV-1 / Q000502:physiology; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D019713:Receptors, CCR5 / Q000737:chemistry / Q000502:physiology; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014779:Virus Replication
D016915:AIDS Vaccines; D010456:Peptides, Cyclic; D019713:Receptors, CCR5; D019718:Receptors, CXCR4