Mechanistic Study and Gene Targeting to Block HIV Assembly by IN-Binding Protein

通过 IN 结合蛋白阻断 HIV 组装的机制研究和基因靶向

基本信息

项目摘要

Despite major advances in treatment, Human Immunodeficiency Virus 1 (HIV-1) remains a significant public health issue that currently has no cure. Lifelong treatment is required due to the remaining latently infected cells. Unlike currently available drugs, a self-sustained therapeutic that targets events undergone by infected cells could potentially control the viral load in patients, leading to a functional cure. The HIV-1 life cycle consists of early events, the events from entry to proviral integration into the genome, and late events, which encompass transcription through budding and virion maturation. HIV-1 assembly, one of the late events, involves sequential assembly of Gag and Gag-Pol structural proteins along with HIV-1 genomic RNA to form assembly intermediate complexes, that eventually reach the plasma membrane to bud out as infectious virions. While much has been studied about assembly and viral determinants required for these events, the nature of assembly intermediates and the association of viral and cellular protein in these complexes is not well understood. Furthermore, while Gag is the major viral structural protein that is involved in assembly, Gag-Pol, which is incorporated at 1:20 ratio to that of Gag, also plays a role in these events. Mutations in Pol portion of Gag-Pol such as integrase (IN) and reverse transcriptase (RT) have been shown to interfere with the assembly events. The role of Gag-Pol or the host factors associated with Pol is largely unknown at this point. My project is focused on understanding of the role of a Pol-binding host factor in assembly and use this knowledge to develop therapeutics to inhibit assembly. . A fragment of the HIV-1 IN-binding host protein, INI1/hSNF5, has been previously shown to inhibit HIV- 1 late events prior to budding. While it is known that the minimal IN-binding fragment of INI1/hSNF5 (termed S6) inhibits late events prior to budding, the exact stage or the mechanism is unknown. In this proposal, I propose (1) examining assembly intermediate complexes to determine if this inhibitory fragment affects assembly complex formation and (2) site-specifically inserting DNA coding for this fragment into the genome of T-cells and assessing off-target effects and ability to inhibit HIV-1 particle production. Determining the effects of S6 on assembly intermediates will shed light on mechanisms of early assembly and improve our knowledge of the role of IN-binding proteins in HIV-1 assembly. Gene therapy approaches to express S6 in T cells hold promising therapeutic potential for HIV-1. Inserting S6 site-specifically, using CRISPR/Cas9, a targeted nuclease that precisely modifies genomes, to inhibit assembly not only provides a novel approach to inhibit assembly, but also helps improve our knowledge of genome engineering to inhibit HIV-1 replication.
尽管在治疗方面取得了重大进展,但人类免疫缺陷病毒1(HIV-1)仍然是一个重大的疾病。 公共卫生问题,目前还没有治愈。需要终身治疗,因为剩余的潜伏期 被感染的细胞与目前可用的药物不同,一种自我维持的治疗药物,靶向患者经历的事件, 受感染的细胞有可能控制患者体内的病毒载量,从而实现功能性治愈。HIV-1的生命周期 包括早期事件,从进入到前病毒整合到基因组中的事件,以及晚期事件, 包括通过出芽和病毒体成熟的转录。HIV-1的组装是晚期事件之一, 包括Gag和Gag-Pol结构蛋白沿着与HIV-1基因组RNA的顺序组装, 组装中间复合物,其最终到达质膜以出芽为感染性病毒体。 虽然已经对这些事件所需的组装和病毒决定簇进行了大量研究,但这些事件的性质仍然是未知的。 组装中间体和病毒和细胞蛋白在这些复合物中的结合不好 明白此外,虽然Gag是参与组装的主要病毒结构蛋白,但Gag-Pol, 其以与Gag的1:20的比例掺入,也在这些事件中起作用。Pol部分的突变 Gag-Pol如整合酶(IN)和逆转录酶(RT)已被证明干扰组装 事件Gag-Pol或与Pol相关的宿主因子的作用在这一点上很大程度上是未知的。我的项目 是集中在了解的作用,一个Pol-binding主机因子在组装和使用这一知识, 研发抑制组装的疗法. HIV-1 IN结合宿主蛋白INI 1/hSNF 5的片段先前已显示抑制HIV-1 IN结合宿主蛋白INI 1/hSNF 5。 1晚事件在萌芽之前。虽然已知INI 1/hSNF 5的最小IN结合片段(称为INI 1/hSNF 5)是一种蛋白质, S6)在出芽之前抑制晚期事件,确切的阶段或机制是未知的。在这份提案中,我 建议(1)检查组装中间体复合物以确定该抑制片段是否影响 组装复合物的形成和(2)将编码该片段的DNA位点特异性地插入到 T细胞和评估脱靶效应和抑制HIV-1颗粒产生的能力。确定影响 S6对组装中间体的研究将有助于阐明早期组装的机制,并提高我们的认识 IN结合蛋白在HIV-1装配中的作用。在T细胞中表达S6的基因治疗方法 HIV-1的治疗潜力。使用CRISPR/Cas9,插入S6位点特异性, 精确修饰基因组的核酸酶抑制组装不仅提供了一种抑制 组装,而且还有助于提高我们的基因组工程知识,以抑制HIV-1复制。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Estah Leah Bock其他文献

Estah Leah Bock的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 2.18万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了