权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TARGETING THE VIRUS ASSEMBLY AND ENTRY PATHWAYS FOR ANTI-HIV GENE THERAPY

针对抗 HIV 基因治疗的病毒组装和进入途径

基本信息

批准号：
8527699
负责人：
Anjali Joshi
金额：
$ 7.55万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527699
关键词：
Adverse effects Affect Anti-HIV Agents CD34 gene Cell Transplantation Cells Complex Development Dominant-Negative Mutation Escape Mutant Future Gagging Gene Transduction Agent Generations Genes Glycoproteins HIV HIV Infections HIV-1 Human In Vitro Infection Integration Host Factors Interphase Cell Intervention Lentivirus Vector Life Cycle Stages Mediating MicroRNAs Mind Morphogenesis Mutate Mutation Nature Pathway interactions Patients Pharmacotherapy Play Proteins RNA Binding RNA Processing Reporting Resistance Role Salvage Therapy Sorting - Cell Movement Staging Stem cell transplant Stem cells TFAP2A gene Terminally Ill Testing Therapeutic Intervention Toxic effect Transcription Factor AP-1 Viral Viral Proteins Viral Vector Virion Virus Virus Assembly Virus Replication cellular transduction chemotherapy design env Gene Products fitness gag Gene Products gene therapy genetic manipulation inhibitor/antagonist mutant new therapeutic target novel particle rev-Responsive Elements small hairpin RNA success tool

项目摘要

DESCRIPTION (provided by applicant): Targeting the HIV entry and assembly pathways holds promise for development of anti- HIV gene therapy vectors as disrupting the virus at multiple stages in the life cycle will likely limit the emergence of resistant mutants. Moreover, recent advances in human CD34+ stem cell transduction and transplantation have paved a way for anti-HIV gene therapy in the near future. These advances have thus prompted a search for new and potent gene therapy targets for suppression of HIV replication. While si/shRNAs against viral and cellular factors have been tested there are a limited number of studies on dominant negative (DN) viral or cellular proteins that can act as HIV inhibitors. In this regard, the Gag and Envelope proteins of HIV-1 remain an attractive yet unexploited target for anti-HIV gene therapy. Both the Gag and envelope proteins play essential roles in completion of the viral life cycle namely via promoting HIV particle assembly/budding or allowing infection into cells respectively. Notably, virus assembly not only requires the viral Gag protein but also numerous host cell factors like Tsg101, Alix, GGAs, Arfs, POSH, AP-1, AP-3 proteins etc to complete virion morphogenesis. Hence, dominant negative forms of the above genes either individually or in combination have the potential to be developed as powerful tools to target HIV-1 replication. Thus, targeting HIV replication via multiple ways will have the advantage of not only halting virus spread rapidly but also restrict the emergence of resistant isolates.

描述（由申请人提供）：针对 HIV 进入和组装途径有望开发抗 HIV 基因治疗载体，因为在生命周期的多个阶段破坏病毒可能会限制耐药突变体的出现。此外，人类CD34+干细胞转导和移植方面的最新进展为不久的将来抗HIV基因治疗铺平了道路。因此，这些进展促使人们寻找新的、有效的基因治疗靶点来抑制艾滋病毒复制。虽然已经测试了针对病毒和细胞因子的 si/shRNA，但针对可充当 HIV 抑制剂的显性失活 (DN) 病毒或细胞蛋白的研究数量有限。在这方面，HIV-1 的 Gag 和 Envelope 蛋白仍然是抗 HIV 基因治疗中一个有吸引力但尚未开发的靶点。 Gag 和包膜蛋白在病毒生命周期的完成中发挥着重要作用，即分别通过促进 HIV 颗粒组装/出芽或允许感染细胞。值得注意的是，病毒组装不仅需要病毒Gag蛋白，还需要许多宿主细胞因子，如Tsg101、Alix、GGAs、Arfs、POSH、AP-1、AP-3蛋白等来完成病毒颗粒形态发生。因此，上述基因的显性失活形式无论是单独还是组合都有可能被开发为针对 HIV-1 复制的强大工具。因此，通过多种方式靶向HIV复制不仅具有阻止病毒快速传播的优势，而且还可以限制耐药菌株的出现。