Therapeutic effect of a gag-nuclease fusion protein against retroviral infection in vivo
Therapeutic effect of a gag-nuclease fusion protein against retroviral infection in vivo
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DOI：
10.1128/jvi.75.15.7030-7041.2001
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发表时间：
2001-08-01
影响因子：
5.4
通讯作者：
Boeke, JD
中科院分区：
文献类型：
--
作者：
Schumann, G;Hermankova, M;Boeke, JD
最近，在开发可以控制但不能治愈逆转录病毒复制的有效联合药物疗法方面取得了显着进展。即使有效，这些药物方案也是有毒的，它们需要苛刻的给药时间表，并且可能出现耐药病毒。因此，对新的基于基因的疗法的需求仍在继续。在一种这样的方法中，衣壳蛋白靶向病毒灭活（CTVI），与病毒外壳蛋白融合的核酸酶在感染的细胞中表达，并在病毒体组装期间被掺入。CTVI可以消除组织培养中感染性小鼠逆转录病毒滴度，在这里，我们描述了表达Moloney小鼠白血病病毒（Mo-MuLV）Gag蛋白与葡萄球菌核酸酶融合蛋白的转基因小鼠，这项工作测试了CTVI在表达内源性Mo-MuLV前病毒拷贝的转基因小鼠中的保护作用，并证明了体内原理验证，表达抗病毒蛋白的小鼠表型正常，证明融合蛋白没有毒性。Mo-MuLV感染在转基因同窝仔中的毒力比非转基因同窝仔低得多，GAG核酸酶表达使血液中的感染滴度降低至10倍，降低了脾肿大和白血病浸润，并使转基因相对于非转基因感染动物的寿命延长至2.5倍。这些结果表明，基于类似融合蛋白的基因疗法，旨在攻击人类免疫缺陷病毒或其他逆转录病毒，可以提供实质性的治疗益处。
Recently, remarkable progress has been made in developing effective combination drug therapies that can control but not cure retroviral replication. Even when effective, these drug regimens are toxic, they require demanding administration schedules, and resistant viruses can emerge. Thus the need for new gene-based therapies continues. In one such approach, capsid-targeted viral inactivation (CTVI), nucleases fused to viral coat proteins are expressed in infected cells and become incorporated during virion assembly. CTVI can eliminate infectious murine retrovirus titer in tissue culture, Here we describe transgenic mice expressing fusions of the Moloney murine leukemia virus (Mo-MuLV) Gag protein to staphylococcal nuclease, This work tests the protective effect and demonstrates in vivo proof-of-principle of CTVI in transgenic mice expressing endogenous proviral copies of Mo-MuLV, The antiviral protein-expressing mice are phenotypically normal, attesting to the lack of toxicity of the fusion protein. The Mo-MuLV infection was much less virulent in transgenic littermates than in nontransgenic littermates, Gag-nuclease expression reduced infectious titers in blood up to 10-fold, decreased splenomegaly and leukemic infiltration, and increased life spans up to 2.5-fold in transgenic relative to nontransgenic infected animals. These results suggest that gene therapies based on similar fusion proteins, designed to attack human immunodeficiency virus or other retroviruses, could provide substantial therapeutic benefits.