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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要/摘要膜相关的环ch（3月）蛋白是环中隐含的环氧蛋白连接酶膜受体的调节。在发现K3和K5之后出现了这个泛素连接酶家族，两个卡波西肉瘤相关的疱疹病毒（KSHV）的病毒三月 - 霍莫尔格斯，这对于逃避宿主通过泛素化并随后删除主要的组织相容性综合体的免疫反应 II（MHC-II）受体来自细胞表面，因此阻断了抗原表现。细胞 3月份的蛋白质家族由11个具有共同结构相似性并包含环形域的成员组成这对于靶膜受体（例如MHC-II）的去除和内在化至关重要。最近的报告结果表明，三月蛋白还可能限制人类免疫缺陷病毒1（HIV-1）感染。 3月1日，2和8通过阻止在病毒信封中掺入HIV-1和其他逆转录病毒发芽的病毒。该提案探讨了三月介导的抗逆转录病毒机制的各个方面以前从未研究过。目前，没有关于抵抗病毒蛋白的信息三月蛋白质。该研究计划的第一个目的是艾滋病毒编码因素的机制在感染期间抵消3月8日。第二个目标检查HIV-1信封的敏感性对三月介导的限制的不同亚型以及来自不同亚型的HIV-1蛋白的能力抵消3月8日。初步研究表明，随着时间的流逝，HIV-1对三月限制具有抵抗力。第三个目标将决定HIV-1基因组的变化，从而使其具有抗性抑制作用。最后，第四个目标将解决另一个三月蛋白在HIV-1感染中的作用。总而言之，这些研究将为三月蛋白的抗逆转录病毒作用提供新的启示，并将解决三月的各个方面先前尚未确定的介导的HIV-1抑制。最后，这些蛋白质具有强大的潜力作为开发抗逆转录病毒疗法的临床靶标。