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：
10408871
负责人：
Melissa E Kane
金额：
$ 39.35万
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/10408871
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.

项目摘要/摘要诸如HIV-1之类的慢病毒在通过劫持中感染非分裂细胞的能力具有独特的效率细胞核细胞质运输途径。灵长类动病毒的核进口受到干扰素可诱导的GTPase MX2，该MX2位于核孔复合物中。但是，该过程 HIV-1利用细胞核细胞质运输以及如何抑制MX2的核进入定义。此外，MX2与其他影响前整合的细胞蛋白之间的关系 HIV-1感染的阶段尚不清楚。我们以前已经证明了MX2的抗病毒活性受细胞类型，细胞周期和HIV-1 capsid- 依赖方式。我们进一步确定MX2抑制非病毒货物中非病毒货物的核细胞流量细胞类型依赖性方式，表明它可能在抗病毒干扰素反应中具有更广泛的功能。这里，我们旨在确定MX2如何定位于核孔复合体，这是核进口途径被MX2抑制，如何影响MX2是核质运输中的异质性，MX2如何影响 HIV-1与其他抗病毒蛋白的相互作用。