Furin-dependent CCL17-fused recombinant toxin controls HTLV-1 infection by targeting and eliminating infected CCR4-expressing cells in vitro and in vivo

Retrovirology

Isao Hamaguchi¹  Kazunari Yamaguchi¹  Arya Biragyn²  Naoki Yamamoto³  Seiji Okada⁵  Kazuhiro Morishita⁶  Kumiko Araki¹  Madoka Kuramitsu¹  Masumichi Saito¹  Kazuya Takizawa¹  Seiji Tateyama⁴  Kazu Okuma¹  Masateru Hiyoshi¹ 

[1] Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama 208-0011, Tokyo, Japan;Immunoregulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore 21224, MD, USA;Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore;Medical Facilities Support Department, Micron Inc., Chiyoda-ku, Tokyo 100-0005, Japan;Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan;Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Kiyotake 889-1692, Miyazaki, Japan

关键词: Furin;    Pseudomonas exotoxin;    CCL17/TARC;    CCR4;    HTLV-1;   

Others  :  1223833
DOI  :  10.1186/s12977-015-0199-8

 received in 2015-03-29, accepted in 2015-08-12,  发布年份 2015

【 摘 要 】

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 furin-dependent manner, indicating the excellent therapeutic potential of TARC–PE38.

【 授权许可】

   
2015 Hiyoshi et al.

【 图 表 】

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