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Retrovirus Structure and Assembly with Inositol Phosphates

逆转录病毒结构和用磷酸肌醇组装

基本信息

批准号：
10872754
负责人：
Robert A Dick
金额：
$ 12.39万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10872754
关键词：
Retrovirus Structure Assembly Inositol Phosphates

项目摘要

Project Summary Assembly of Gag into an immature virus particle is a critical step in the viral life cycle. After assembly the immature virus particle goes through a process called maturation which is required to produce infectious virus particles. We recently showed that the small cellular molecule, inositol hexakisphosphate (IP6) is required for both assembly and maturation, and that decreasing IP6 levels in cells severely reduces the formation of infectious virus. While we know have a “big picture” view of how IP6 affects HIV, there is still a great deal we don’t understand. This proposal seeks to characterize the mechanism of IP6 induced immature assembly, how IP6 promotes mature assembly, and if these assembly steps can be targeted by antiretrovirals. Furthermore, preliminary work suggests that IP6 is a cofactor for other retroviruses, and so this proposal will test the hypothesis that IP6 as a retroviral cofactor is evolutionarily conserved. Specific Aim 1 is to further characterize how IP6 binds and promotes HIV-1 assembly and maturation. High resolution cryo-EM analysis will be performed on IP6 assembled mature virus-like particles with and without cellular proteins that are known to bind to the viral core in cells. The effect of maturation inhibitors Bevirimat and PF-46396, which bind to the same region as IP6, on IP6 binding and enhanced assembly will be determined using a series of biochemical assays. In addition, this aim will test the hypothesis that IP6 is utilized by other lentiviruses. For example, preliminary data suggest that the Equine Infectious Anemia Virus also employs IP6 for the production of infectious virus. Specific Aim 2 is to determine if and how IP6 is utilized by retroviruses outside of the lentivirus genus. Preliminary data shows that the alpha retrovirus Rous sarcoma virus (RSV), and the delta retrovirus Human T-Cell Leukemia Virus (HTLV) both utilize IP6. We will identify the site of IP6 action on both viruses using biochemical and structural approaches. We will also screen viruses from the other retroviral genera to determine if they also utilize IP6. Specific Aim 3 is to determine if and how IP6 related compounds affect HIV-1 immature assembly, maturation, and mature assembly. Working with a collaborator, we will synthesize and screen IP6-like compounds in assembly and maturation assays. This aim will help to determine if compounds that target the IP6 binding site are a feasible antiretroviral strategy.

项目摘要将Gag组装成未成熟的病毒颗粒是病毒生命周期中的关键步骤。后组装未成熟的病毒颗粒要经过一个称为成熟的过程，产生感染性病毒颗粒的能力我们最近发现，分子，肌醇六磷酸（IP 6）是组装和成熟所必需的，降低细胞中IP 6水平会严重减少感染性病毒的形成。虽然我们我知道，对于IP 6如何影响艾滋病病毒，我们有一个“大局”的观点，但还有很多我们不知道的明白该建议旨在描述IP 6诱导不成熟的机制，组装，IP 6如何促进成熟的组装，以及这些组装步骤是否可以通过抗逆转录病毒药物此外，初步工作表明，IP 6是其他因此，这项提议将检验IP 6作为逆转录病毒辅因子的假设，进化上保守。具体目标1是进一步表征IP 6如何结合和促进 HIV-1的组装和成熟。将在IP 6上进行高分辨率冷冻EM分析组装的成熟病毒样颗粒，具有和不具有已知结合至细胞中的病毒核心成熟抑制剂Bevirimat和PF-46396的作用，其结合到与IP 6相同的区域对IP 6结合和增强的组装的影响将使用一系列生化检测。此外，这一目标将检验IP 6被以下方面利用的假设：其他慢病毒例如，初步数据表明，马传染性贫血 Virus还使用IP 6来生产传染性病毒。具体目标2是确定以及慢病毒属以外的逆转录病毒如何利用IP 6。初步数据显示 α逆转录病毒劳斯肉瘤病毒（RSV）和δ逆转录病毒人类T细胞白血病病毒（HTLV）都利用IP 6。我们将确定IP 6对这两种病毒采取行动的地点使用生物化学和结构方法。我们还将筛选病毒从其他逆转录病毒属，以确定它们是否也利用IP 6。具体目标3是确定是否以及如何 IP 6相关化合物影响HIV-1未成熟组装、成熟和成熟组装。与合作者合作，我们将合成和筛选组装中的IP 6样化合物，成熟测定。这一目标将有助于确定靶向IP 6结合位点的化合物是否是一种可行的抗逆转录病毒策略。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Unconventional stabilization of the human T-cell leukemia virus type 1 immature Gag lattice.

人类 T 细胞白血病病毒 1 型未成熟 Gag 晶格的非常规稳定。

DOI：
10.1101/2023.07.24.548988
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Obr,Martin;Percipalle,Mathias;Chernikova,Darya;Yang,Huixin;Thader,Andreas;Pinke,Gergely;Porley,Dario;Mansky,LouisM;Dick,RobertA;Schur,FlorianKm
通讯作者：
Schur,FlorianKm

PI(4,5)P2 Clustering and Its Impact on Biological Functions.

PI(4,5)P2 聚类及其对生物功能的影响。