Antibody to the central region of human T‐lymphotropic virus type 1 gp46 is associated with the progression of adult T‐cell leukemia

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 is spread by cellto-cell transmission via the gp46-197 region, Asp197 to Leu216, on the envelope protein gp46. In the present study, we revealed a positive correlation between the appearance of an antibody recognizing the gp46-197 region (anti-gp46-197 antibody) and the severity of ATL. The prevalence and titer of the anti-gp46-197 antibody were found to be elevated along with the progression of ATL. In serial samples obtained from a single patient, the anti-gp46-197 antibody was detected before treatment in acute phase, then diminished after allogeneic bone marrow transplantation, to which the patient had a complete response. However, the antibody appeared again before a relapse, along with an increase of the serum-soluble interleukin-2 receptor level and proviral load. The results from the other six patients also indicate that seroconversion of this antibody was synchronized with the deterioration of ATL. Taken (1,2) ATL is characterized by tumor cells with mature T-lymphocyte phenotypes, onset in middle-aged or elderly individuals infected with HTLV-1 through breast milk, and by the presence of leukemic cells with multilobulated nuclei bearing chromosomal abnormalities. It has been observed that the HTLV-1 provirus integrates randomly into the human genome in asymptomatic carriers (AC), resulting in only a smear pattern of proviral DNA by Southern blot analysis. However, monoclonal integration bands detected by Southern blot analysis indicate clonal proliferation of neoplastic leukemia/ lymphoma cells infected with HTLV-1. Patients with ATL are classified into four clinical subtypes based on Shimoyama's diagnostic criteria: acute, lymphoma, chronic and smoldering. Patients with chronic and smoldering ATL are in a basically healthy state, but often progress to acute ATL after a long incubation. In lymphoma-type ATL, few abnormal cells are observed in peripheral white blood cells, but patients die in the short course, as in the acute type. Recently, therapeutic trials of allogeneic hematopoietic stem cell transplantation for ATL treatment have been reported, with such treatment leading some ATL patients to long-lasting complete remission with no detection of HTLV-1 provirus, (4) but the overall prognosis continues to be poor. There is no evidence of virus in plasma in vivo or HTLV-1 infection as a result of blood transfusion in patients who received only plasma products from seropositive blood donors. (5) Thus, it is apparent that HTLV-1 transmission occurs via cell-cell contact and is inefficient by cell-free body fluids. Previously, we demonstrated that the gp46 -197 region, corresponding to the region from Asp197 to Leu216 on envelope protein gp46 of HTLV-1, functions as a receptor binding site in cell-to-cell infection of HTLV-1.(6) The 71-kDa heat shock cognate protein (HSC70) acts as an HTLV-1 receptor on the cell surface by binding to the gp46 -197 region. (7,8) Recently, it was reported...

Involvement of molecular mimicry between human T‐cell leukemia virus type 1 gp46 and osteoprotegerin in induction of hypercalcemia

“…(21,22) In the present study, we observed hypercalcemia in the rabbits, which produced anti-gp46-197 Ab recognizing both of the terminal regions of gp46-197. The epitopes of anti-gp46-197 Ab from the dead rabbit were quite distinct from that from the surviving rabbits (Fig.…”

“…The synthetic peptides used in this study are listed elsewhere. (21)(22)(23) Enzyme-linked immunoabsorbent assay (ELISA). To detect the anti-gp46-197 Ab, we used a modified ELISA without blocking by biomaterials, an unblocked ELISA, as described previously.…”

“…(20) Previously, we reported that the appearance of anti-gp46-197 Ab, an antibody recognizing the Asp197 to region, was synchronized with the deterioration of ATL, (21) and proposed that the antibody possibly cross-reacted with human cellular component(s) and that the interaction might be associated with the pathogenesis. (22) In the present study, rabbits that produced the anti-gp46-197 Ab recognizing amino-terminal region of gp46-197 died from hypercalcemia soon after a booster administration of gp46-197 synthetic peptide. The administration of the peptide into rats caused a significant decrease of the bone mineral density (BMD) and the inhibition of the bone growth of femora along with a rise in the serum calcium level.…”

A Dramatic Response to Denosumab: Protracted Hypocalcemia Related to Human T-Cell Lymphotropic virus type 1-Associated Adult T-Cell Leukemia/Lymphoma

“…In addition, tumor cells directly induce osteoclast activation by increasing receptor activator of nuclear factor kappa-Β (RANK) signaling in the bone through multiple mechanisms including secretion of receptor activator of nuclear factor kappa-Β ligand (RANK-L) and proinflammatory cytokines such as macrophage inflammatory protein-1α (7) and the protein Wnt-5a. This leads to enhanced osteoclastogenesis by increasing RANK expression (8), and secretion of the viral protein gp46 which acts as an antagonist for osteoprotegerin (9).…”

Síntese de sais de piridínio novos catalisadores de transferência de fase

“…A desprotonação de grupos metílicos de sais de piridínio formando anidrobases e posterior reação com eletrófilos é conhecida 144 • Assim, a adição de acrilato de metila, em presença de trietilamina, ao sal de N-benzil-4-picolínio formou o diaduto de Michael130. Com base em tais precedentes de literatura, acreditamos que os baixos rendimentos obtidos na adição de acetamidomalonato de dietila à chalcona poderiam ser explicados pela reação do aceptor de Michael com o sal de piridínio testado como catalisador.…”