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Inhibition of lentiviral nuclear import pathways by Mx2

Mx2 对慢病毒核输入途径的抑制

基本信息

批准号：
10615182
负责人：
Melissa E Kane
金额：
$ 39.46万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-21 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615182
关键词：
Address Affect Amino Acid Sequence Antiviral Agents Binding Proteins Capsid Capsid Proteins Cell Cycle Cell Line Cell Nucleus Cells Chimeric Proteins Complex DNA Dependence Development Event Genome Guanosine Triphosphate Phosphohydrolases HIV Infections HIV-1 Heterogeneity Immune Importins Individual Infection Innate Immune Response Innate Immune System Interferons Interphase Cell Investigation Length Lentivirus Life Cycle Stages Mediating Modeling Molecular N-terminal Nuclear Nuclear Import Nuclear Localization Signal Nuclear Pore Nuclear Pore Complex Nuclear Pore Complex Proteins Outcome Pathway interactions Pattern recognition receptor Predisposition Primate Lentiviruses Process Proteins Reporting Role Signal Transduction TRIM Gene Testing Viral Viral Physiology Viral Proteins Virus Virus Diseases Virus Replication Work cell type cofactor insight knock-down mutant novel therapeutics nucleic acid detection protein protein interaction response sensor trafficking viral DNA

项目摘要

PROJECT SUMMARY/ABSTRACT Lentiviruses such as HIV-1 are uniquely efficient in their ability to infect non-dividing cells through the hijacking of cellular nucleocytoplasmic trafficking pathways. Nuclear import of primate lentiviruses is inhibited by the interferon inducible GTPase Mx2, which localizes to the nuclear pore complex. However, the process by which HIV-1 utilizes cellular nucleocytoplasmic trafficking and how nuclear entry is inhibited by Mx2 remain poorly defined. Furthermore, the relationship between Mx2 and other cellular proteins that affect the pre-integration stages of HIV-1 infection is not understood. We have previously demonstrated that the antiviral activity of Mx2 is affected by cellular nucleocytoplasmic trafficking pathways in a cell-type, cell-cycle, and HIV-1 capsid- dependent manner. We further determined that Mx2 inhibits nucleocytoplasmic trafficking of non-viral cargo in a cell-type dependent manner, indicating that it may have broader functions in antiviral interferon responses. Here, we aim to determine how Mx2 is localized to the nuclear pore complex, the nuclear import pathways that are inhibited by Mx2, how Mx2 is affected be heterogeneity in nucleocytoplasmic trafficking, and how Mx2 affects the interaction of HIV-1 with other antiviral proteins.

项目总结/摘要慢病毒，如HIV-1，是唯一有效的能力，感染非分裂细胞通过劫持细胞核质运输途径。灵长类动物慢病毒的核输入受到干扰素诱导型GT3 Mx2，其定位于核孔复合物。然而， HIV-1利用细胞核质运输，Mx2如何抑制核进入仍然很差定义了此外，Mx2和其他影响预整合的细胞蛋白质之间的关系， HIV-1感染的阶段尚不清楚。我们以前已经证明，Mx2的抗病毒活性受细胞类型、细胞周期和HIV-1衣壳中细胞核质运输途径的影响，依赖的方式。我们进一步确定，Mx2抑制非病毒货物的核质运输，细胞类型依赖性的方式，表明它可能具有更广泛的抗病毒干扰素反应的功能。在这里，我们的目标是确定Mx2是如何定位于核孔复合物的，核输入途径是受Mx2抑制，Mx2如何受到影响是核质运输的异质性，以及Mx2如何影响 HIV-1与其他抗病毒蛋白的相互作用。