SERINCs and Nef Function

SERINC 和 Nef 函数

• 批准号: 9915890
• 负责人: HEINRICH GOTTLINGER
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915890
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; Antibodies; Antiviral Agents; Apical; Binding; Capsid; Cell surface; Cells; Clathrin; Complex; Cytoplasm; Dependence; Dominant-Negative Mutation; Down-Regulation; Dynamin 2; Endocytosis; Excision; Family member; Glycoproteins; HIV-1; Integral Membrane Protein; Integration Host Factors; Investigation; Mediating; Membrane; Pathogenicity; Phase; Phosphatidylserines; Predisposition; Production; Property; Proteins; Public Health; Recycling; Reverse Transcription; Serine; Surface; TFAP2A gene; Viral; Viral Proteins; Viral load measurement; Virion; Virus; combat; experimental study; nef Protein; novel; particle; prevent; trafficking; uptake; viral envelope lipids

ABSTRACT The accessory HIV-1 protein Nef is a major pathogenicity determinant that is crucial for high virus loads and for progression to AIDS. Nef increases the specific infectivity of HIV-1 virions, but the mechanism has long remained enigmatic. We have recently identified the multipass transmembrane proteins SERINC3 and SERINC5 as novel anti-viral factors whose down- regulation by Nef accounts for its effect on HIV-1 infectivity. SERINC5 in particular strongly inhibits the infectivity of Nef-deficient HIV-1 progeny virions. HIV-1 Nef induces the removal of SERINC3 and SERINC5 from the surface of virus-producing cells, which prevents their incorporation into HIV-1 virions and consequently counteracts their inhibitory effects on HIV-1 infectivity. However, it remains unclear how SERINCs affect HIV-1 virions. We propose to investigate what determines the susceptibility of HIV-1 envelope glycoproteins to SERINCs, whether SERINCs account for the ability of Nef to protect a membrane-proximal region of gp41, and whether SERINCs affect the viral lipid envelope. It also remains unclear what step during the early phase of HIV-1 replication is inhibited by virion-associated SERINCs. We propose to investigate the hypothesis that SERINCs inhibit the translocation of the mature viral core into target cells. Finally, we propose to investigate what step of SERINC trafficking is affected by Nef, and what determines the ability of Nef to selectively downregulate those SERINC family members that inhibit HIV-1. These studies are significant, because SERINC3 and SERINC5 are highly expressed in primary HIV-1 target cells. Inhibiting their downregulation by Nef is thus a potential strategy to combat HIV/AIDS.

抽象的 辅助HIV-1蛋白NEF是主要的致病性决定因素，对于高 病毒负荷和向艾滋病进展。 NEF增加了HIV-1病毒体的特定感染性， 但是这种机制长期以来一直是神秘的。我们最近确定了多通 跨膜蛋白Serinc3和Serinc5是新的抗病毒因素，其下降 - NEF的调节说明了其对HIV-1感染性的影响。 Serinc5特别强烈 抑制NEF缺陷型HIV-1后代病毒体的感染性。 HIV-1 NEF诱导去除 Serinc3和Serinc5来自产生病毒的细胞表面，这阻止了它们 纳入HIV-1病毒体，因此抵消了其对HIV-1的抑制作用 感染力。然而，尚不清楚序列环节如何影响HIV-1病毒体。我们建议 研究是什么决定了HIV-1包膜糖蛋白对序列的敏感性， Serincs是否解释了NEF保护GP41的膜透明区域的能力， 以及序列是否影响病毒脂质包膜。目前尚不清楚在 HIV-1复制的早期阶段被与病毒体相关的序列抑制。我们建议 研究序列抑制成熟病毒核心易位的假设 靶细胞。最后，我们建议调查序列贩运的哪一步受到影响 NEF，以及什么决定NEF选择性下调那些序列家族的能力 抑制HIV-1的成员。这些研究很重要，因为Serinc3和Serinc5是 在原代HIV-1靶细胞中高度表达。因此，抑制NEF的下调是一个 对抗艾滋病毒/艾滋病的潜在策略。

项目成果

Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5.

在缺乏 SERINC3 和 SERINC5 的情况下，Nef 有效增强 HIV-1 复制。

• DOI: 10.1128/mbio.01071-19
• 发表时间: 2019
• 期刊: mBio
• 影响因子: 6.4
• 作者: Wu,Yuanfei;Olety,Balaji;Weiss,EricR;Popova,Elena;Yamanaka,Hikaru;Göttlinger,Heinrich
• 通讯作者: Göttlinger,Heinrich

A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef.

• DOI: 10.1016/j.celrep.2017.12.082
• 发表时间: 2018-01-23
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Dai W;Usami Y;Wu Y;Göttlinger H
• 通讯作者: Göttlinger H

AP-2 Adaptor Complex-Dependent Enhancement of HIV-1 Replication by Nef in the Absence of the Nef/AP-2 Targets SERINC5 and CD4.

• DOI: 10.1128/mbio.03382-22
• 发表时间: 2023-02-28
• 期刊: mBio
• 影响因子: 6.4
• 作者: Olety B;Usami Y;Wu Y;Peters P;Göttlinger H
• 通讯作者: Göttlinger H

HIV-1 propagation is highly dependent on basal levels of the restriction factor BST2.

• DOI: 10.1126/sciadv.abj7398
• 发表时间: 2021-10-29
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Olety B;Peters P;Wu Y;Usami Y;Göttlinger H
• 通讯作者: Göttlinger H