SERINCs and Nef Function

SERINC 和 Nef 函数

• 批准号: 9204014
• 负责人: HEINRICH GOTTLINGER
• 金额: $ 43.14万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204014
• 关键词: AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Affect; Antibodies; 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; nef Protein; novel; particle; prevent; research study; 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.

摘要 辅助HIV-1蛋白Nef是一个主要的致病决定因素，对高致病性 病毒载量和发展成为艾滋病的原因。NEF增加了HIV-1病毒粒子的特异性传染性， 但其机制长期以来一直是个谜。我们最近发现了多通道 跨膜蛋白SERINC3和SERINC5作为新的抗病毒因子，其下调 Nef的调节解释了它对HIV-1传染性的影响。SERINC5特别强烈 抑制Nef缺陷的HIV-1子代病毒粒子的传染性。HIV-1 Nef诱导去除 SERINC3和SERINC5从病毒产生细胞的表面，这阻止了他们的 掺入HIV-1病毒粒子，从而抵消其对HIV-1的抑制作用 传染性。然而，目前尚不清楚SERINC如何影响HIV-1病毒粒子。我们建议 研究是什么决定了HIV-1包膜糖蛋白对SERINC的敏感性， SERINC是否解释了Nef保护gp41膜近端区域的能力， 以及SERINC是否影响病毒的脂膜。目前还不清楚在什么步骤中 HIV-1复制的早期阶段被病毒相关的SERINC抑制。我们建议 研究SERINC抑制成熟病毒核心转位到 目标单元格。最后，我们建议调查SERINC贩运的哪个步骤受到 以及是什么决定了Nef选择性下调这些SERINC家族的能力 抑制HIV-1的成员。这些研究意义重大，因为SERINC3和SERINC5是 在原代HIV-1靶细胞中高表达。因此，抑制Nef下调它们的调控是一种 防治艾滋病毒/艾滋病的潜在战略。