MARCH Proteins, Members of a Host Protein Family that Targets HIV-1

MARCH 蛋白，靶向 HIV-1 的宿主蛋白家族成员

• 批准号: 10455259
• 负责人: Spyridon Stavrou
• 金额: $ 39.19万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-12 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455259
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Retroviral Agents; Antigen Presentation; Antiviral Agents; Applications Grants; Bypass; Cell Membrane Proteins; Cell Surface Proteins; Cell Surface Receptors; Cell fusion; Cell membrane; Cell physiology; Cells; Cellular Membrane; Clinical; Development; Drug Targeting; Excision; Exclusion; Family; Fingers; Genetic; Genetic Polymorphism; Genome; Genomics; Glycoproteins; Goals; HIV; HIV Infections; HIV-1; Homologous Gene; Human Herpesvirus 8; Immune response; Infection; Integration Host Factors; Light; MHC Class II Genes; Major Histocompatibility Complex; Mediating; Membrane; Mutate; Mutation; Play; Predisposition; Production; Protein Family; Proteins; Reagent; Regulation; Reporting; Research; Resistance; Retroviridae; Retroviridae Infections; Role; Series; Structure; System; Tetanus Helper Peptide; Therapeutic; Time; Ubiquitin family; Ubiquitination; United States National Institutes of Health; Viral; Viral Proteins; Virion; Virus; drug development; env Genes; genome sequencing; grasp; in vitro Assay; macrophage; member; monocyte; novel therapeutic intervention; pressure; prevent; programs; receptor; receptor binding; ubiquitin ligase; ubiquitin-protein ligase; virus envelope; vpr Genes

Project Summary/ Abstract Membrane Associated RING CH (MARCH) proteins are RING E3 ubiquitin ligases that are implicated in the regulation of membrane receptors. This family of ubiquitin ligases emerged after the discovery of K3 and K5, two viral MARCH-homologues in Kaposi’s sarcoma associated herpesvirus (KSHV), which are critical in evading the host’s immune response by ubiquitinating and subsequently removing the major histocompatibility complex class II (MHC-II) receptors from the surface of the cells and therefore blocking antigen presentation. The cellular MARCH family of proteins consists of 11 members that share structural similarity and contain a RING-CH domain that is essential for the removal and internalization of target membrane receptors (e.g. MHC-II). Recent reports showed that MARCH proteins can also potently restrict human immunodeficiency virus 1 (HIV-1) infection. MARCH1, 2 and 8 restrict HIV-1 and other retroviruses by blocking the incorporation of the viral envelope in the budding virions. This proposal explores aspects of the MARCH-mediated antiretroviral mechanism that have never been previously studied. Currently, there is no information concerning a viral protein that counteracts MARCH proteins. The first aim of this research plan examines the mechanism by which an HIV encoded factor counteracts MARCH8 during infection. The second aim examines the susceptibility of HIV-1 envelopes from different subtypes to MARCH-mediated restriction as well as the ability of HIV-1 proteins from different subtypes to counteract MARCH8. Preliminary studies show that HIV-1 over time becomes resistant to MARCH restriction. The third aim will determine the changes in the HIV-1 genome that render it resistant to MARCH inhibition. Finally, the fourth aim will address the role of the other MARCH proteins on HIV-1 infection. In summary, these studies will shed new light on the anti-retroviral role of MARCH proteins and will address aspects of MARCH- mediated HIV-1 inhibition that have not been previously determined. Finally, these proteins have strong potential as clinical targets for the development of antiretroviral therapeutics.

项目总结/摘要 膜相关RING CH（MARCH）蛋白是RING E3泛素连接酶，其涉及细胞膜的形成。 膜受体的调节。这个泛蛋白连接酶家族是在发现K3和K5之后出现的， 卡波西肉瘤相关疱疹病毒（KSHV）中的病毒MARCH同源物，这在逃避 通过泛素化和随后去除主要组织相容性复合物类的宿主免疫应答 II（MHC-II）受体从细胞表面，因此阻断抗原呈递。蜂窝 MARCH蛋白家族由11个成员组成，这些成员具有结构相似性并包含RING-CH结构域 其对于靶膜受体（例如MHC-II）的去除和内化是必需的。最近的报告 研究表明，MARCH蛋白也可以有效地限制人类免疫缺陷病毒1（HIV-1）感染。 MARCH 1、2和8通过阻断病毒包膜结合到 萌芽病毒体该提案探讨了MARCH介导的抗逆转录病毒机制的各个方面， 以前从未被研究过。目前，还没有关于病毒蛋白质的信息， MARCH蛋白。这项研究计划的第一个目标是研究艾滋病毒编码因子的机制， 在感染期间抵消MARCH 8。第二个目的是检查HIV-1包膜的易感性， 不同亚型对MARCH介导的限制以及来自不同亚型的HIV-1蛋白的能力 3月8日，初步研究表明，随着时间的推移，HIV-1会对MARCH限制产生抗药性。 第三个目标是确定HIV-1基因组中使其对MARCH抑制剂具有抗性的变化。 最后，第四个目标将解决其他MARCH蛋白在HIV-1感染中的作用。总而言之， 研究将揭示MARCH蛋白的抗逆转录病毒作用，并将解决MARCH- 介导的HIV-1抑制作用之前尚未确定。最后，这些蛋白质具有强大的潜力， 作为抗逆转录病毒疗法的临床靶点。