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.
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.
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DOI：
10.1128/jvi.01885-17
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发表时间：
2018-02-15
影响因子：
5.4
通讯作者：
Hamaguchi I
中科院分区：
文献类型：
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作者：
Tezuka K;Okuma K;Kuramitsu M;Matsuoka S;Tanaka R;Tanaka Y;Hamaguchi I
人类 T 细胞白血病病毒 1 型 (HTLV-1) 感染会导致成人 T 细胞白血病 (ATL)，这种疾病通常对目前可用的治疗方法产生耐药性，且预后非常差。为了防止携带者发生 ATL，控制感染个体中 HTLV-1 感染的细胞非常重要。因此，迫切需要建立专门针对感染细胞的药物的新疗法。本研究旨在通过生成重组水疱性口炎病毒 (rVSV) 来开发一种潜在的治疗方法，该病毒缺乏包膜糖蛋白 G，而是编码具有人葡萄糖转运蛋白 1 (GLUT1)、神经毡蛋白 1 (NRP1) 或硫酸乙酰肝素蛋白聚糖 (HSPG)（包括多聚糖 1）的 HTLV-1 受体 (SDC1)，分别指定为 VSVΔG-GL、VSVΔG-NP 或 VSVΔG-SD。为了增强rVSV对HTLV-1感染细胞的感染性，我们还构建了具有两个或三个受体基因组合的rVSV，分别命名为VSVΔG-GLN和VSVΔG-GLNS。本研究表明 VSVΔG-GL、VSVΔG-NP、VSVΔG-GLN 和 VSVΔG-GLNS 对 HTLV-1 包膜 (Env) 表达细胞具有趋向性。值得注意的是，在培养条件下接种VSVΔG-GL或VSVΔG-NP显着消除了HTLV-1感染的细胞。此外，在HTLV-1感染的人源化小鼠模型中，VSVΔG-NP能够有效防止HTLV-1诱导的外周白细胞增多，并消除淋巴组织中HTLV-1感染的Env表达细胞。总之，设计表达 HTLV-1 主要受体（尤其是人 NRP1）的 rVSV 可能代表一种候选药物，有潜力开发针对 HTLV-1 从头感染的独特病毒疗法。重要性 尽管目前有几种抗 ATL 疗法可用，但 ATL 仍然经常对治疗方法产生耐药性，并且其预后仍然很差。控制 HTLV-1 从头感染或在载体中扩增 HTLV-1 感染的细胞对于预防 ATL 的发展具有很大的希望。在这项研究中，我们开发了 rVSV，通过用 VSV 基因组中的 HTLV-1 受体基因替换 G 基因，特异性靶向并杀死 HTLV-1 Env 表达细胞（不是 ATL 细胞，它们通常在体内不表达 Env）。值得注意的是，设计表达人类 NRP1 的 rVSV 在体外和体内控制了 HTLV-1 感染的 Env 表达细胞的数量，这表明本方法可能是 HTLV-1 携带者中新型抗 HTLV-1 病毒疗法的有希望的候选者，包括作为针对 ATL 发展的预防性治疗。
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.