Optimizing the Targeting of Mouse Parvovirus 1 to Murine Melanoma Selects for Recombinant Genomes and Novel Mutations in the Viral Capsid Gene.
Optimizing the Targeting of Mouse Parvovirus 1 to Murine Melanoma Selects for Recombinant Genomes and Novel Mutations in the Viral Capsid Gene.
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DOI：
10.3390/v10020054
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发表时间：
2018-01-30
期刊：
影响因子：
--
通讯作者：
Tattersall P
中科院分区：
文献类型：
--
作者：
Marr M;D'Abramo A;Pittman N;Agbandje-McKenna M;Cotmore SF;Tattersall P
将病毒增强的免疫原性与直接递送免疫调节分子相结合将代表一种新的黑色素瘤治疗方式，并且需要开发能够优先靶向黑色素瘤细胞的新病毒载体。在这里，我们探索使用啮齿动物原细小病毒靶向小鼠黑色素瘤模型 B16F10 的细胞。小鼠细小病毒 1 (MPV1) 的未克隆原液显示出一定的功效，并且在靶细胞中连续传代后，其功效显着增强。起始病毒库和选定病毒库的基因的分子克隆揭示了相当大的序列多样性。嵌合体分析将大部分感染性改善归因于主要外壳蛋白基因VP2的产物，其中选择了氨基酸变化的连锁块和两个明显自发突变中的一个或另一个。基因内嵌合体表明这些代表了可分离的成分，两者都有助于增强感染。克隆病毒感染生化参数的比较表明，VP2变化引起的增强作用是在病毒与细胞表面结合并渗透到细胞内后发生的。 MPV1 的计算机同源模型的构建允许将这些变化放置在衣壳内，并揭示了衣壳参与感染启动的方面，这些方面以前未被认识到。
Combining virus-enhanced immunogenicity with direct delivery of immunomodulatory molecules would represent a novel treatment modality for melanoma, and would require development of new viral vectors capable of targeting melanoma cells preferentially. Here we explore the use of rodent protoparvoviruses targeting cells of the murine melanoma model B16F10. An uncloned stock of mouse parvovirus 1 (MPV1) showed some efficacy, which was substantially enhanced following serial passage in the target cell. Molecular cloning of the genes of both starter and selected virus pools revealed considerable sequence diversity. Chimera analysis mapped the majority of the improved infectivity to the product of the major coat protein gene, VP2, in which linked blocks of amino acid changes and one or other of two apparently spontaneous mutations were selected. Intragenic chimeras showed that these represented separable components, both contributing to enhanced infection. Comparison of biochemical parameters of infection by clonal viruses indicated that the enhancement due to changes in VP2 operates after the virus has bound to the cell surface and penetrated into the cell. Construction of an in silico homology model for MPV1 allowed placement of these changes within the capsid shell, and revealed aspects of the capsid involved in infection initiation that had not been previously recognized.
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影响因子：
3.3
作者：
Engelsma, Dieuwke;Valle, Noelia;Fornerod, Maarten
通讯作者：
Fornerod, Maarten
影响因子：
3.7
作者：
Cotmore, SF;D'Abramo, AM;Tattersall, P
通讯作者：
Tattersall, P
影响因子：
3.7
作者：
Farr, GA;Tattersall, P
通讯作者：
Tattersall, P
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.8
作者：
Arnold, K;Bordoli, L;Schwede, T
通讯作者：
Schwede, T