Affiliation:
1. Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Tokyo, Japan
2. Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
Abstract
ABSTRACT
Human T-cell leukemia virus type 1 (HTLV-1) infection causes adult T-cell leukemia (ATL), which is frequently resistant to currently available therapies and has a very poor prognosis. To prevent the development of ATL among carriers, it is important to control HTLV-1-infected cells in infected individuals. Therefore, the establishment of novel therapies with drugs specifically targeting infected cells is urgently required. This study aimed to develop a potential therapy by generating recombinant vesicular stomatitis viruses (rVSVs) that lack an envelope glycoprotein G and instead encode an HTLV-1 receptor with human glucose transporter 1 (GLUT1), neuropilin 1 (NRP1), or heparan sulfate proteoglycans (HSPGs), including syndecan 1 (SDC1), designated VSVΔG-GL, VSVΔG-NP, or VSVΔG-SD, respectively. In an attempt to enhance the infectivity of rVSV against HTLV-1-infected cells, we also constructed rVSVs with a combination of two or three receptor genes, designated VSVΔG-GLN and VSVΔG-GLNS, respectively. The present study demonstrates VSVΔG-GL, VSVΔG-NP, VSVΔG-GLN, and VSVΔG-GLNS have tropism for HTLV-1 envelope (Env)-expressing cells. Notably, the inoculation of VSVΔG-GL or VSVΔG-NP significantly eliminated HTLV-1-infected cells under the culture conditions. Furthermore, in an HTLV-1-infected humanized mouse model, VSVΔG-NP was capable of efficiently preventing HTLV-1-induced leukocytosis in the periphery and eliminating HTLV-1-infected Env-expressing cells in the lymphoid tissues. In summary, an rVSV engineered to express HTLV-1 primary receptor, especially human NRP1, may represent a drug candidate that has potential for the development of unique virotherapy against HTLV-1
de novo
infection.
IMPORTANCE
Although several anti-ATL therapies are currently available, ATL is still frequently resistant to therapeutic approaches, and its prognosis remains poor. Control of HTLV-1
de novo
infection or expansion of HTLV-1-infected cells in the carrier holds considerable promise for the prevention of ATL development. In this study, we developed rVSVs that specifically target and kill HTLV-1 Env-expressing cells (not ATL cells, which generally do not express Env
in vivo
) through replacement of the G gene with HTLV-1 receptor gene(s) in the VSV genome. Notably, an rVSV engineered to express human NRP1 controlled the number of HTLV-1-infected Env-expressing cells
in vitro
and
in vivo
, suggesting the present approach may be a promising candidate for novel anti-HTLV-1 virotherapy in HTLV-1 carriers, including as a prophylactic treatment against the development of ATL.
Funder
Japan Agency for Medical Research and Development
MEXT | Japan Society for the Promotion of Science
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
Cited by
9 articles.
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