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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：
10326898
负责人：
Melissa E Kane
金额：
$ 38.84万
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/10326898
关键词：
Address Affect Antiviral Agents Binding Capsid Capsid Proteins Cell Cycle Cell Line Cell Nucleus Cells Chimeric Proteins Complex DNA Dependence Development Equilibrium 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 Methods 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 Virus Virus Diseases Virus Replication Work cell type cofactor insight knock-down mutant novel therapeutics nucleic acid detection 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.

项目概要/摘要 HIV-1 等慢病毒通过劫持感染非分裂细胞的能力非常高效细胞核细胞质运输途径的研究。灵长类慢病毒的核输入被抑制干扰素诱导型 GTPase Mx2，定位于核孔复合体。然而，该过程 HIV-1 利用细胞核细胞质运输以及 Mx2 如何抑制核进入仍不清楚定义的。此外，Mx2 和其他影响预整合的细胞蛋白之间的关系 HIV-1 感染的各个阶段尚不清楚。我们之前已经证明 Mx2 的抗病毒活性受细胞类型、细胞周期和 HIV-1 衣壳中细胞核细胞质运输途径的影响依赖方式。我们进一步确定 Mx2 抑制非病毒货物的核细胞质运输细胞类型依赖性方式，表明它在抗病毒干扰素反应中可能具有更广泛的功能。这里，我们的目标是确定 Mx2 如何定位于核孔复合体，即核输入途径被 Mx2 抑制，Mx2 如何受到核细胞质运输异质性的影响，以及 Mx2 如何影响 HIV-1 与其他抗病毒蛋白的相互作用。