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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

基本信息

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
项目类别：
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

项目摘要

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，因此统称为干扰素。 IFN刺激基因（ISG）;然而，许多基因不受IFN直接调控，表征了值得注意的是，已知这些细胞因子中的一些调节脂质和/或膜性质，从而破坏HIV和其他病毒的复制。最近的两个例子是TIM（T- 细胞免疫球蛋白和粘蛋白结构域）和SERINC（丝氨酸蛋白酶）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。有趣的是，我们的初步数据和最近发表在《自然》杂志上的两份报告显示，慢病毒Nef 蛋白质有效地拮抗TIM和SERINC的限制。此外，我们最近观察到， SERINC蛋白增强TIM-1阻断HIV-1释放的能力，SERINC通过稳定HIV-1释放来实现这一点。病毒生产细胞中的TIM表达。在这个应用中，我们提出了几个新的假设测试解决TIM、SERINC、PS和Nef之间可能存在的联系。目标1将确定HIV-1 Nef 通过调节TIM-1的合成和运输，拮抗TIM介导的病毒释放抑制和PS。目的2将集中于了解内源性SERINC蛋白在CD 4 + T细胞中的作用，调节TIM表达和稳定性，以及调节病毒生产细胞和病毒感染细胞中的脂质。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蛋白如何降低- 调节这一过程以促进HIV-1的产生和感染。从拟议的实验结果将为TIM、SERINC和HIV Nef之间的相互作用提供了新的和统一的机制见解，增强我们对病毒-宿主相互作用和艾滋病发病机制的理解。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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