Involvement of molecular mimicry between human T-cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemia.
Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL), frequently associated with hypercalcemia and bone destruction. A positive correlation between the appearance of an antibody recognizing the central region (Asp197 to Leu216) on Gp46, gp46-197, and the severity of ATL has been demonstrated. In this study, five male Nihon Hakusyoku rabbits were immunized with a synthetic peptide corresponding to the gp46-197 region to clarify its action and mechanism. Two of the rabbits showed piloerection, anorexia, and somnolence, and died soon after booster administration. The serum calcium level of the dead rabbits was significantly high, compared to those of surviving rabbits. Interestingly, amino acid sequences homologous with gp46-197 were found in the carboxyl-terminal half of osteoprotegerin (OPG), an osteoclast inhibitory factor. To confirm the effect of the gp46-197 region on osteogenesis in vivo, the peptide was intraperitoneally administered to male Sprague-Dawley rats. The administration of the gp46-197 peptide resulted in a decrease of bone mineral density (BMD), a significant increase of serum calcium level, and inhibition of normal bone growth in both short- and long-term experiments. In rats, femoral growth inhibition by the gp46-197 peptide was restored by the coadministration of recombinant human OPG. Improvement by OPG in the adverse effect indicates that the central region of HTLV-1 Gp46 acts as an antagonist for OPG and leads to hypercalcemia.
Sagara
Yasuko
Y
Department of Research, Japanese Red Cross Fukuoka Blood Center, Chikushino, Fukuoka, Japan. y-sagara@fukuoka.bc.jrc.or.jp
Inoue
Yukiko
Y
Sagara
Yasuhiro
Y
Kashiwagi
Seizaburo
S
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D015686:Gene Products, env / Q000235:genetics / Q000276:immunology*; D015481:HTLV-I Antibodies / Q000276:immunology*; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000150:complications / Q000276:immunology*; D008297:Male; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D053244:Osteoprotegerin / Q000235:genetics / Q000276:immunology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000276:immunology*; D017386:Sequence Homology, Amino Acid
D015686:Gene Products, env; D015481:HTLV-I Antibodies; D053244:Osteoprotegerin; D015682:Retroviridae Proteins, Oncogenic; C055266:gp46 protein, Human T-cell leukemia virus type I