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- Title
Furin‑dependent CCL17‑fused recombinant toxin controls HTLV‑1 infection by targeting and eliminating infected CCR4‑expressing cells in vitro and in vivo.
- 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
Background: 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. Results: 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. Conclusions: TARC–PE38 robustly controls HTLV-1 infection by eliminating infected cells in both a CCR4- and furindependent manner, indicating the excellent therapeutic potential of TARC–PE38.
- Publication
Retrovirology, 2015, Vol 12, Issue 1, p73
- ISSN
1742-4690
- Publication type
Article
- DOI
10.1186/s12977-015-0199-8