| First Author | Tezuka K | Year | 2018 |
| Journal | J Virol | Volume | 92 |
| Issue | 4 | PubMed ID | 29212930 |
| Mgi Jnum | J:303404 | Mgi Id | MGI:6512155 |
| Doi | 10.1128/JVI.01885-17 | Citation | Tezuka K, et al. (2018) Control of Human T-Cell Leukemia Virus Type 1 (HTLV-1) Infection by Eliminating Envelope Protein-Positive Cells with Recombinant Vesicular Stomatitis Viruses Encoding HTLV-1 Primary Receptor. J Virol 92(4) |
| abstractText | 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 VSVDeltaG-GL, VSVDeltaG-NP, or VSVDeltaG-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 VSVDeltaG-GLN and VSVDeltaG-GLNS, respectively. The present study demonstrates VSVDeltaG-GL, VSVDeltaG-NP, VSVDeltaG-GLN, and VSVDeltaG-GLNS have tropism for HTLV-1 envelope (Env)-expressing cells. Notably, the inoculation of VSVDeltaG-GL or VSVDeltaG-NP significantly eliminated HTLV-1-infected cells under the culture conditions. Furthermore, in an HTLV-1-infected humanized mouse model, VSVDeltaG-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. |
