SERINCs and Nef Function

SERINC 和 Nef 函数

• 批准号: 9295964
• 负责人: HEINRICH GOTTLINGER
• 金额: $ 41.49万
• 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/9295964
• 关键词: AIDS/HIV problem; 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; 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.

摘要 HIV-1的辅助蛋白Nef是一个主要的致病性决定因子，对于HIV-1的高致病性至关重要。 病毒载量和进展为艾滋病。Nef增加了HIV-1病毒粒子的特异性感染性， 但其机制一直是个谜我们最近发现了多通道 SERINC 3和SERINC 5作为新的抗病毒因子， Nef的调节解释了其对HIV-1感染性的影响。Serinc 5特别强烈 抑制Nef缺陷型HIV-1子代病毒粒子的感染性。HIV-1 Nef诱导去除 SERINC 3和SERINC 5从病毒产生细胞的表面分离，这阻止了它们在细胞中的表达。 掺入HIV-1病毒体，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的易感性， SERINC是否解释了Nef保护gp 41的膜近端区域的能力， 以及SERINC是否影响病毒脂质包膜。目前还不清楚， HIV-1复制的早期阶段被病毒体相关的SERINC抑制。我们建议 研究丝氨酸蛋白酶抑制成熟病毒核心易位到 靶细胞最后，我们建议调查什么步骤的SERINC贩运的影响， Nef，是什么决定了Nef选择性下调那些SERINC家族的能力？ 抑制HIV-1的成员。这些研究意义重大，因为SERINC 3和SERINC 5是 在原代HIV-1靶细胞中高度表达。因此，通过Nef抑制它们的下调是一种有效的方法。 防治艾滋病毒/艾滋病的潜在战略。