Furin-dependent CCL17-fused recombinant toxin controls HTLV-1 infection by targeting and eliminating infected CCR4-expressing cells in vitro and in vivo.
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.
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. mhiyoshi@niid.go.jp.
Masateru
M
Hiyoshi
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. kokuma@niid.go.jp.
Kazu
K
Okuma
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. tateyama@micron-kobe.com.|Medical Facilities Support Department, Micron Inc., Chiyoda-ku, Tokyo, 100-0005, Japan. tateyama@micron-kobe.com.
Seiji
S
Tateyama
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. kaztaki@nirs.go.jp.
Kazuya
K
Takizawa
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. saitomas@niid.go.jp.
Masumichi
M
Saito
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. mkura@niid.go.jp.
Madoka
M
Kuramitsu
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. karaki@niid.go.jp.
Kumiko
K
Araki
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan. kmorishi@med.miyazaki-u.ac.jp.
Kazuhiro
K
Morishita
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan. okadas@kumamoto-u.ac.jp.
Seiji
S
Okada
Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore. naoki_yamamoto@nuhs.edu.sg.
Naoki
N
Yamamoto
Immunoregulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, 21224, USA. biragyna@grc.nia.nih.gov.
Arya
A
Biragyn
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. kyama@niid.go.jp.
Kazunari
K
Yamaguchi
Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. 130hama@niid.go.jp.
Isao
I
Hamaguchi
D000328:Adult; D000818:Animals; D058345:Asymptomatic Infections / Q000628:therapy; D045744:Cell Line, Tumor; D054414:Chemokine CCL17 / Q000494:pharmacology*; D018925:Chemokines / Q000235:genetics; D004195:Disease Models, Animal; D005098:Exotoxins / Q000494:pharmacology*; D045683:Furin / Q000235:genetics* / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000821:virology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D051379:Mice; D011533:Proviruses / Q000187:drug effects / Q000502:physiology; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D020298:U937 Cells
D054414:Chemokine CCL17; D018925:Chemokines; D005098:Exotoxins; D054398:Receptors, CCR4; D011993:Recombinant Fusion Proteins; C000592234:TARC-PE38 fusion protein; D045683:Furin