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首页> 外文学位 >Molecular characterization of the HIV-1 Vpu protein and its role in antagonizing the cellular restriction factor Bst-2/tetherin both in vitro and in vivo.
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Molecular characterization of the HIV-1 Vpu protein and its role in antagonizing the cellular restriction factor Bst-2/tetherin both in vitro and in vivo.

机译：HIV-1 Vpu蛋白的分子特征及其在体外和体内拮抗细胞限制性因子Bst-2 / tetherin的作用。

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摘要

The cellular restriction factor BST-2/tetherin exerts a late stage anti-viral activity against enveloped viruses, retaining newly formed virions at the cell surface and effectively lowering virus output from infected cells. It is also a key player in the regulation of interferon production through binding to ILT7 on plasmacytoid dendritic cells, which also impacts the virus-host interaction. A number of pathogenic viruses have been found to express counter strategies to tetherin, with the Human Immunodeficiency Virus 1 using Vpu. This suggests that a strong selective pressure exists for HIV to block tetherin expression.;This potent antagonism of tetherin by Vpu could pose as a novel target for development of additional therapeutic compounds to combat viral infection. The accessory proteins of HIV are not the main targets for current HAART therapy of infected individuals. New compounds targeting these proteins could dramatically aid in the fight against HIV infection, especially considering these proteins are responsible for mediating cellular conditions, permitting efficient viral replication and dissemination.;Current systems to investigate tetherin countermeasures are limited since in vitro cell cultures do not adequately recapitulate certain aspects of viral replication or innate immune activation. Additionally, in vivo testing using SIV or SHIV derivatives in monkey models of infection can be misrepresentative of HIV infections in humans. We are using humanized mice as a small animal model to study HIV-1 infections in vivo. The mice are created by engraftment of NOD/SCID/IL2Rgamma-/- mice with human hematopoietic stem cells, resulting in the development of mature human CD4+ T cells that support infection by HIV-1.;We have created a series of Vpu deficient viruses in the NL4.3 backbone, using either a null mutant or a specific point mutation (A18H) that blocks tetherin antagonism without affecting other functions of Vpu, such as CD4 degradation. Interestingly, neither of these Vpu mutations had any effect on virus replication that was apparent in the Jurkat-based JLTRG reporter cell line, but caused a decrease in replicative fitness in PBMC cultures. By infecting humanized mice with these viruses which vary in their ability to counteract tetherin, we were able to gain a better understanding on the role of tetherin restriction during the course of an in vivo infection. Together, these studies were meant to better characterize the interaction between tetherin and its viral antagonist Vpu by both determining the significance of restriction during infection, and discovering novel ways to disrupt this interaction through therapeutic intervention.
机译：细胞限制因子BST-2 / tetherin对包膜病毒发挥后期抗病毒活性，将新形成的病毒体保留在细胞表面，并有效降低感染细胞的病毒输出。它也是通过结合浆细胞样树突状细胞上的ILT7来调节干扰素产生的关键角色，这也影响了病毒与宿主的相互作用。已发现许多致病性病毒与使用Vpu的人类免疫缺陷病毒1表达了对抗tetherin的对抗策略。这表明对HIV有强大的选择性压力来阻止tetherin的表达。Vpu对tetherin的强力拮抗作用可能会成为开发其他治疗化合物以对抗病毒感染的新靶标。 HIV的辅助蛋白并不是当前HAART治疗感染个体的主要目标。针对这些蛋白质的新化合物可以极大地帮助抗击HIV感染，特别是考虑到这些蛋白质负责介导细胞状况，允许有效的病毒复制和传播。;由于体外细胞培养不足，目前用于研究系链素对策的系统有限概括了病毒复制或先天免疫激活的某些方面。此外，在猴子的感染模型中使用SIV或SHIV衍生物的体内测试可能会误导人类的HIV感染。我们正在使用人源化的小鼠作为小型动物模型来研究体内HIV-1感染。这些小鼠是通过将NOD / SCID / IL2Rgamma-/-小鼠植入人类造血干细胞而产生的，从而导致了成熟的支持CD-1感染的人类CD4 + T细胞的发育。我们已经创建了一系列Vpu缺陷病毒在NL4.3主链中，使用无效突变体或特定点突变（A18H）来阻止tetherin拮抗作用，而不会影响Vpu的其他功能，例如CD4降解。有趣的是，这些Vpu突变均未对病毒复制产生任何影响，这在基于Jurkat的JLTRG报告基因细胞系中很明显，但会导致PBMC培养物中复制适应性的降低。通过用这些病毒对抗人脑中的etherether的感染来感染人源化小鼠，我们能够更好地了解在体内感染过程中etherinin限制的作用。总之，这些研究旨在通过确定感染过程中限制作用的重要性，并发现通过治疗干预破坏这种相互作用的新方法，从而更好地表征tetherin及其病毒拮抗剂Vpu之间的相互作用。

著录项

  • 作者

    Haworth, Kevin G.;

  • 作者单位

    University of Southern California.;

  • 授予单位 University of Southern California.;
  • 学科 Biology Virology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 155 p.
  • 总页数 155
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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