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

MARCH 蛋白，针对 HIV 的宿主蛋白家族成员

基本信息

批准号：
10543550
负责人：
Spyridon Stavrou
金额：
$ 39.53万
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：
2021-12-22 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543550
关键词：
Acquired Immunodeficiency Syndrome Affect Anti-Retroviral Agents Antigen Presentation 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 Histocompatibility Antigens Class II Homologous Gene Human Herpesvirus 8 Immune response Infection Integration Host Factors MHC Class II Genes Macrophage Mediating Membrane Mutate Mutation Play Predisposition Production Protein Family Proteins Reagent Regulation Reporting Research Resistance Retroviridae Retroviridae Infections Role System Therapeutic Time Ubiquitin family Ubiquitination United States National Institutes of Health Viral Viral Proteins Virion Virus antiviral drug development env Genes genome sequencing member monocyte novel therapeutic intervention pressure prevent programs receptor receptor binding ubiquitin ligase ubiquitin-protein ligase vpr Genes

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.

项目概要/摘要膜相关 RING CH (MARCH) 蛋白是 RING E3 泛素连接酶，与该泛素连接酶家族是在 K3 和 K5 这两种酶发现后出现的。卡波西肉瘤相关疱疹病毒 (KSHV) 中的病毒 MARCH 同源物，对于逃避病毒至关重要通过泛素化并随后去除主要组织相容性复合体类来调节宿主的免疫反应 II (MHC-II) 受体来自细胞表面，因此阻断抗原呈递。 MARCH 蛋白质家族由 11 个成员组成，它们具有结构相似性并包含 RING-CH 结构域这对于目标膜受体（例如 MHC-II）的去除和内化至关重要。研究表明，MARCH 蛋白还可以有效限制人类免疫缺陷病毒 1 (HIV-1) 感染。 MARCH1、2 和 8 通过阻止病毒包膜掺入细胞中来限制 HIV-1 和其他逆转录病毒该提案探讨了 MARCH 介导的抗逆转录病毒机制的各个方面。目前尚未研究过有关病毒蛋白的信息。 MARCH 蛋白该研究计划的第一个目标是检查 HIV 编码因子的机制。在感染期间抵消 MARCH8 第二个目标是检查 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 蛋白的能力初步研究表明，随着时间的推移，HIV-1 对 MARCH 限制产生抵抗力。第三个目标是确定 HIV-1 基因组的变化，使其能够抵抗 MARCH 抑制。最后，第四个目标将解决其他 MARCH 蛋白对 HIV-1 感染的作用。总之，这些。研究将为 MARCH 蛋白的抗逆转录病毒作用提供新的线索，并将解决 MARCH- 的各个方面最后，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目标。