TIM-mediated Inhibition of HIV Release: Cooperation with SERINC and Antagonism by Nef

TIM 介导的 HIV 释放抑制：与 SERINC 的合作和 Nef 的拮抗

• 批准号: 10242695
• 负责人: Shan-Lu Liu
• 金额: $ 33.15万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242695
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anabolism; Antiviral Agents; Apoptotic; Binding; Biological Process; CD4 Positive T Lymphocytes; Categories; Cell membrane; Cells; Data; Ebola virus; Epithelial Cells; Equine Infectious Anemia Virus; Family; Fluorescence Resonance Energy Transfer; Genes; HIV; HIV Infections; HIV-1; Immune response; Immunofluorescence Immunologic; Immunoglobulins; Impairment; Infection; Integration Host Factors; Interferons; Intrinsic factor; Knowledge; Lead; Link; Lipids; Lymphoid Cell; Mediating; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Microdomains; Microscopy; Modeling; Molecular; Mucins; Murine leukemia virus; Nature; Pathogenesis; Pathogenicity; Peripheral Blood Mononuclear Cell; Phosphatidylserines; Physiological; Primates; Process; Production; Property; Protein Family; Proteins; Publishing; Reporting; Role; Serine; Structure; T-Lymphocyte; Techniques; Tertiary Protein Structure; Testing; Viral; Virion; Virus; Virus Diseases; Work; experimental study; immunoregulation; insight; knock-down; macrophage; monocyte; mutant; nef Protein; novel; novel strategies; particle; trafficking; viral entry inhibitor; virus host interaction

The majority of antiviral restriction factors are interferon (IFN) inducible, and are thus collectively referred to as IFN-stimulated genes (ISGs); many, however, are NOT directly regulated by IFN and remain poorly characterized. Notably, some of these cellular factors are known to modulate lipids and/or membrane properties, thereby disrupting the replication of HIV and other viruses. Two recent examples from this category are TIM (T- cell immunoglobulin and mucin domain) and SERINC (serine incorporator) family proteins, which directly interact with or possibly regulate the synthesis of phosphatidylserine (PS), thus inhibiting HIV release or infectivity. Interestingly, our preliminary data and two recent reports published in Nature showed that the lentiviral Nef proteins effectively antagonize the restriction by TIMs and SERINCs. Moreover, we have recently observed that SERINC proteins potentiate the ability of TIM-1 to block HIV-1 release and that SERINCs do this by stabilizing the TIM expression in the viral producer cells. In this application, we propose to test several novel hypotheses that address the possible link between TIM, SERINC, PS and Nef. Aim 1 will determine how HIV-1 Nef antagonizes TIM-mediated inhibition of viral release through modulating the synthesis and trafficking of TIM-1 and PS. Aim 2 will focus on understanding of the role of endogenous SERINC proteins in CD4+ T cells that regulates the TIM expression and stability, as well as in modulating lipids in the viral producer cell and viral particles, collectively contributing to the inhibition of HIV-1 release and replication. Aim 3 will define the molecular interplay between SERINC and TIM proteins in viral producer cells, and dissect how HIV-1 Nef protein down- modulates this process to promote HIV-1 production and infection. Results from the proposed experiments will provide novel and unified mechanistic insights into the interplay between TIM, SERINC and HIV Nef, and will enhance our understanding of virus-host interaction and AIDS pathogenesis.

大多数抗病毒限制因子是干扰素（IFN）诱导的，因此统称为 作为 IFN 刺激基因 (ISG)；然而，许多不受干扰素直接调节并且仍然很差 特点。值得注意的是，已知其中一些细胞因子可以调节脂质和/或膜特性， 从而破坏艾滋病毒和其他病毒的复制。此类别中最近的两个示例是 TIM (T- 细胞免疫球蛋白和粘蛋白结构域）和 SERINC（丝氨酸掺入子）家族蛋白，它们直接相互作用 与或可能调节磷脂酰丝氨酸（PS）的合成，从而抑制HIV释放或感染性。 有趣的是，我们的初步数据和最近在《自然》杂志上发表的两份报告表明，慢病毒 Nef 蛋白质有效地对抗 TIM 和 SERINC 的限制。此外，我们最近观察到 SERINC 蛋白增强了 TIM-1 阻断 HIV-1 释放的能力，而 SERINC 是通过稳定 病毒生产细胞中的 TIM 表达。在此应用中，我们建议测试几个新颖的假设 解决了 TIM、SERINC、PS 和 Nef 之间可能存在的联系。目标 1 将确定 HIV-1 Nef 如何 通过调节 TIM-1 的合成和运输来拮抗 TIM 介导的病毒释放抑制 和PS。目标 2 将重点了解 CD4+ T 细胞中内源性 SERINC 蛋白的作用， 调节 TIM 表达和稳定性，以及调节病毒生产细胞和病毒中的脂质 颗粒，共同有助于抑制 HIV-1 的释放和复制。目标 3 将定义分子 病毒生产细胞中 SERINC 和 TIM 蛋白之间的相互作用，并剖析 HIV-1 Nef 蛋白如何下调 调节这一过程以促进 HIV-1 的产生和感染。拟议实验的结果将 为 TIM、SERINC 和 HIV Nef 之间的相互作用提供新颖且统一的机制见解，并将 增强我们对病毒与宿主相互作用和艾滋病发病机制的了解。

项目成果

SARS-CoV-2 spreads through cell-to-cell transmission.

• DOI: 10.1073/pnas.2111400119
• 发表时间: 2022-01-04
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Zeng C;Evans JP;King T;Zheng YM;Oltz EM;Whelan SPJ;Saif LJ;Peeples ME;Liu SL
• 通讯作者: Liu SL

Role of host factors in SARS-CoV-2 entry.

• DOI: 10.1016/j.jbc.2021.100847
• 发表时间: 2021-07
• 期刊: The Journal of biological chemistry
• 作者: Evans JP;Liu SL
• 通讯作者: Liu SL

CD4-Dependent Modulation of HIV-1 Entry by LY6E.

LY6E 对 HIV-1 进入的 CD4 依赖性调节。

• DOI: 10.1128/jvi.01866-18
• 发表时间: 2019
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Yu,Jingyou;Liang,Chen;Liu,Shan-Lu
• 通讯作者: Liu,Shan-Lu

SERINC proteins potentiate antiviral type I IFN production and proinflammatory signaling pathways.

• DOI: 10.1126/scisignal.abc7611
• 发表时间: 2021-09-14
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Zeng, Cong;Waheed, Abdul A.;Li, Tianliang;Yu, Jingyou;Zheng, Yi-Min;Yount, Jacob S.;Wen, Haitao;Freed, Eric O.;Liu, Shan-Lu
• 通讯作者: Liu, Shan-Lu