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Control of HTLV-1 Infection by Eliminating Envelope Protein-Positive Cells with Recombinant Vesicular Stomatitis Viruses Encoding HTLV-1 Primary Receptor.

Control of HTLV-1 Infection by Eliminating Envelope Protein-Positive Cells with Recombinant Vesicular Stomatitis Viruses Encoding HTLV-1 Primary Receptor.
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Tezuka K, Okuma K, Kuramitsu M, Matsuoka S, Tanaka R, Tanaka Y, Hamaguchi I,


Tezuka K, Okuma K, Kuramitsu M, Matsuoka S, Tanaka R, Tanaka Y, Hamaguchi I, (click to view)

Tezuka K, Okuma K, Kuramitsu M, Matsuoka S, Tanaka R, Tanaka Y, Hamaguchi I,

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Journal of virology 2017 12 06() pii 10.1128/JVI.01885-17

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infection causes adult T-cell leukemia (ATL), which is frequently resistant to current 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 HTLV-1 receptor(s) with human glucose transporter 1 (GLUT1), neuropilin 1 (NRP1), or heparan sulfate proteoglycans (HSPGs) including syndecan 1 (SDC1), designated as 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 as VSVΔG-GLN and VSVΔG-GLNS, respectively. The current study demonstrated 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 in 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.IMPORTANCEAlthough several anti-ATL therapies are currently available, ATL is still frequently resistant to therapeutic approaches and its prognosis remains poor. Control of de novo HTLV-1 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.

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