Title |
Furin-dependent CCL17-fused recombinant toxin controls HTLV-1 infection by targeting and eliminating infected CCR4-expressing cells in vitro and in vivo
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Published in |
Retrovirology, August 2015
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DOI | 10.1186/s12977-015-0199-8 |
Pubmed ID | |
Authors |
Masateru Hiyoshi, Kazu Okuma, Seiji Tateyama, Kazuya Takizawa, Masumichi Saito, Madoka Kuramitsu, Kumiko Araki, Kazuhiro Morishita, Seiji Okada, Naoki Yamamoto, Arya Biragyn, Kazunari Yamaguchi, Isao Hamaguchi |
Abstract |
Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) infection. However, there are no therapies to prevent ATL development in high-risk asymptomatic carriers. To develop a therapy targeting HTLV-1-infected cells that are known to express CCR4 frequently, we tested whether truncated Pseudomonas exotoxin (PE38) fused to a CCR4 ligand, CCL17/thymus and activation-regulated chemokine (TARC), selectively eliminates such cells. Our data show that TARC-PE38 efficiently killed HTLV-1-infected cell lines. It also shrank HTLV-1-associated solid tumors in an infected-cell-engrafted mouse model. In HTLV-1-positive humanized mice, TARC-PE38 markedly inhibited the proliferation of HTLV-1-infected human CD4(+)CD25(+) or CD4(+)CD25(+)CCR4(+) cells and reduced the proviral loads (PVLs) in peripheral blood mononuclear cells (PBMCs). Importantly, TARC-PE38 significantly reduced the PVLs in PBMCs obtained from asymptomatic carriers. We show that the cytotoxicity of TARC-PE38 is mediated by the expression of the proprotein convertase, furin. The expression of furin was enhanced in HTLV-1-infected cells and correlated positively with PVLs in HTLV-1-infected individuals, suggesting that infected cells are more susceptible to TARC-PE38 than normal cells. TARC-PE38 robustly controls HTLV-1 infection by eliminating infected cells in both a CCR4- and furin-dependent manner, indicating the excellent therapeutic potential of TARC-PE38. |
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Science communicators (journalists, bloggers, editors) | 1 | 14% |
Mendeley readers
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Professor | 2 | 13% |
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Neuroscience | 1 | 6% |
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