Molecular mechanism of selective HIV-1 genome packaging

HIV-1基因组选择性包装的分子机制

基本信息

  • 批准号:
    10326908
  • 负责人:
  • 金额:
    $ 23.63万
  • 依托单位:
  • 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:
    2021-05-24 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

Abstract Virtually every step of HIV-1 replication as well as numerous cellular antiviral defense mechanisms are regulated by viral and cellular RNA-binding proteins (RBPs) that recognize distinct sequence or structural features on viral RNAs. One such interaction takes place between the HIV-1 major structural protein, Gag, and the viral genomic RNA. Gag packages two copies of an unspliced positive strand viral genome in particles, which are selected from a pool of cellular and spliced viral mRNAs in excess. How viral genomes are selected for packaging and why only two copies are packaged in a single virus particle remain poorly understood. By extension of findings from simple retroviruses, such as murine leukemia virus (MLV), it has long been thought that HIV-1 selective genome packaging is similarly regulated by a cis-acting packaging signal, Psi (Ψ), located within the 5’ untranslated region of the genome. However, unlike MLV, disruption of regions in Ψ only modestly impacts packaging and regions outside of the Ψ sequence might contribute to genome encapsidation. Thus the precise rules that govern HIV-1 selective genome packaging still remain poorly understood. HIV-1 genome has an unusually biased nucleotide composition, rich in adenosines (~36%) and poor in cytosines (~18%). We have previously discovered that Gag binding to the HIV-1 genome is highly dynamic and undergoes several changes coincident with its membrane binding, multimerization, and proteolytic maturation. In particular, we found that while cytosolic Gag bound to guanosine-rich sequences, its binding preference shifted towards sequences with adenosine-rich nucleotide composition at the plasma membrane concomitant with its multimerization. In this application, we propose to test the novel idea that the overall nucleotide content of the HIV-1 genome contributes to its selective packaging. We will conduct a series of genetic approaches in which the nucleocapsid (NC) domain of Gag is replaced by heterologous RNA-binding domains and by determining the efficiency with which minimal genomes with A-rich vs. A-poor nucleotide content are packaged into virions (Aim 1). Through replacement of NC by heterologous RNA-binding domains and increasing NC copy number per Gag molecule, we propose to determine whether dimeric genome packaging is driven by specificity, affinity and avidity of Gag towards viral RNAs (Aim 2). Overall, this project will provide novel insight into mechanisms of selective genome packaging. Understanding this process is not only significant from a basic molecular biology standpoint but will also impact gene therapy and CRISPR-based engineering tools which depend on retroviral systems for efficient delivery into host cells.
摘要

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)

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Sebla B. Kutluay其他文献

Interview with a Retrovirologist: Sebla B. Kutluay in conversation with Carol Carter
  • DOI:
    10.1186/s12977-021-00562-4
  • 发表时间:
    2021-07-01
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Carol Carter;Sebla B. Kutluay
  • 通讯作者:
    Sebla B. Kutluay
Advantage of urine based molecular diagnosis of Zika virus
  • DOI:
    10.1007/s11255-016-1406-9
  • 发表时间:
    2016-08-27
  • 期刊:
  • 影响因子:
    1.900
  • 作者:
    Laura E. Lamb;Sarah N. Bartolone;Sebla B. Kutluay;Daniela Robledo;Alexandra Porras;Mauricio Plata;Michael B. Chancellor
  • 通讯作者:
    Michael B. Chancellor
CARD8 inflammasome mediates pyroptosis of HIV-1-infected cells by sensing viral protease activity
CARD8炎性体通过感知病毒蛋白酶活性介导HIV-1感染细胞的焦亡
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Qiankun Wang;H. Gao;K. Clark;Pengfei Tang;Gray H. Harlan;Sebla B. Kutluay;C. DeSelm;R. Presti;L. Shan
  • 通讯作者:
    L. Shan
HIV-1 capsid stability and reverse transcription are finely balanced to minimize sensing of reverse transcription products emvia/em the cGAS-STING pathway
HIV-1 衣壳稳定性和逆转录精细平衡,以尽量减少通过 cGAS-STING 途径对逆转录产物的感知
  • DOI:
    10.1128/mbio.00348-24
  • 发表时间:
    2024-03-29
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Jenna E. Eschbach;Maritza Puray-Chavez;Shawn Mohammed;Qiankun Wang;Ming Xia;Lin-Chen Huang;Liang Shan;Sebla B. Kutluay
  • 通讯作者:
    Sebla B. Kutluay
IDENTIFYING THE RNA TARGETS OF RNA BINDING PROTEINS WITH CLIP.
使用 Clip 识别 RNA 结合蛋白的 RNA 靶标。
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Christian Shema Mugisha;Kasyap Tenneti;Sebla B. Kutluay
  • 通讯作者:
    Sebla B. Kutluay

Sebla B. Kutluay的其他文献

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{{ truncateString('Sebla B. Kutluay', 18)}}的其他基金

Allosteric integrase inhibitor effects on human T-cell leukemia virus infection
变构整合酶抑制剂对人T细胞白血病病毒感染的影响
  • 批准号:
    10451085
  • 财政年份:
    2022
  • 资助金额:
    $ 23.63万
  • 项目类别:
Allosteric integrase inhibitor effects on human T-cell leukemia virus infection
变构整合酶抑制剂对人T细胞白血病病毒感染的影响
  • 批准号:
    10550267
  • 财政年份:
    2022
  • 资助金额:
    $ 23.63万
  • 项目类别:
Molecular mechanism of selective HIV-1 genome packaging
HIV-1基因组选择性包装的分子机制
  • 批准号:
    10409845
  • 财政年份:
    2021
  • 资助金额:
    $ 23.63万
  • 项目类别:
Regulation and Targeting of HIV-1 Integrase-RNA Interactions
HIV-1 整合酶-RNA 相互作用的调控和靶向
  • 批准号:
    10402641
  • 财政年份:
    2017
  • 资助金额:
    $ 23.63万
  • 项目类别:
REGULATION AND TARGETING OF HIV-1 INTEGRASE-RNA INTERACTIONS
HIV-1 整合酶-RNA 相互作用的调控和靶向
  • 批准号:
    10062475
  • 财政年份:
    2017
  • 资助金额:
    $ 23.63万
  • 项目类别:
Regulation and Targeting of HIV-1 Integrase-RNA Interactions
HIV-1 整合酶-RNA 相互作用的调控和靶向
  • 批准号:
    10520066
  • 财政年份:
    2017
  • 资助金额:
    $ 23.63万
  • 项目类别:
REGULATION AND TARGETING OF HIV-1 INTEGRASE-RNA INTERACTIONS
HIV-1 整合酶-RNA 相互作用的调控和靶向
  • 批准号:
    9271492
  • 财政年份:
    2017
  • 资助金额:
    $ 23.63万
  • 项目类别:

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