HIV-1 evasion of cytosolic factors
HIV-1逃避胞质因子
基本信息
- 批准号:10014688
- 负责人:
- 金额:$ 13.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Antiviral ResponseBindingCapsidCapsid ProteinsCell NucleusCellsComplexCoupledCyclic GMPCyclophilin ADNADNA receptorDendritic CellsDetectionDissociationDockingEXO1 geneExonucleaseGenomeHIVHIV-1Immune responseImpairmentInfectionInnate Immune ResponseIntegration Host FactorsInterferonsKineticsLeadLinkMammalian CellMitogen-Activated Protein KinasesMutationNF-kappa BNuclear PoreNucleic AcidsPathway interactionsPharmaceutical PreparationsPlayProcessProteinsRetroviridaeReverse TranscriptionRoleSignal TransductionSimplexvirusSubfamily lentivirinaeTREX1 geneTRIM5 geneVariantViralViral GenomeViral Reverse TranscriptionVirionVirusds-DNAgag Gene Productsgenomic RNAinterestmacrophagemammalian genomenucleic acid detectionpathogenprematurepreventreceptorrepairedresponsesensorviral DNAviral detection
项目摘要
The mammalian genome encodes a variety of pathogen recognition receptors (PRRs) specifically involved in the recognition of nucleic acids. Efforts to identify sensors and decipher the mechanisms underlying the innate immune responses that follow nucleic acid detection have largely revolved around studying the interactions of viruses and mammalian cells. Viruses replicate their genomes within host cells and must avoid detection of their nucleic acids by the host cell. The lentivirus HIV-1 is no exception. HIV-1 converts its ssRNA genome into a linear dsDNA within a complex of virion proteins that facilitates the import of the vDNA into the host nucleus where it is integrated into the host genome. Upon entry into host cells, HIV-1 genomic RNA is surrounded by a core composed primarily of CA. Before the HIV-1 core is imported into the nucleus, it appears to shed at least a portion of its CA molecules in a process known as uncoating. Uncoating is thought to be required for the dsDNA contained in the PIC to engage and pass through the host NPC. The precise mechanism and kinetics of HIV-1 uncoating remain unclear. There is evidence to suggest that HIV-1 uncoats after completing reverse transcription and docking at the NPC, suggesting that reverse transcription and uncoating are tightly coupled. It is during the uncoating process that the HIV-1 reverse transcription products would be susceptible to sensing by host cell innate signaling machinery. Thus, the viral and host factors that contribute to HIV uncoating are of particular interest. The mechanism of CA loss during HIV-1 infection appears to be a regulated process. Certain mutations in CA have been shown to negatively impact overall stability of the core and are thought to lead to premature uncoating. In addition, CA variants that either enhance or reduce the stability of the core impair reverse transcription, reinforcing the idea that reverse transcription and uncoating are tightly coupled. Although uncoating has not been directly linked to the induction of innate immune responses in cells, several studies have implicated CA. The retroviral restriction factor TRIM5 was found to initiate MAP kinase and NF-kB signaling in response to sensing of HIV-1 CA. Studies in dendritic cells have shown that newly synthesized HIV-1 CA has a role in the stimulation of an IFN response. Capsid proteins from other viruses have been shown to play a role in preventing type I IFN induction. Degradation of Herpes Simplex Virus capsid led to detection of viral DNA by macrophages. In addition, MLV glycosylated Gag protein was shown to enhance the stability of the viral core and prevent detection of viral reverse transcription products by host cytosolic sensors. There is evidence that HIV-1 reverse transcription products are able to trigger an innate immune response during infection, and it is reasonable to predict that HIV-1 CA prevents the detection of viral DNA prior to uncoating. Cells deficient in the DNA 3' repair exonuclease 1 (TREX1) produce high levels of type I IFN in response to HIV-1 infection, suggesting that viral DNA products can stimulate an immune response if they are not degraded by this exonuclease. In addition, a recent study identified cyclic-GMP-AMP synthase (cGAS) as an HIV-1 DNA sensor whose activation leads to type I IFN induction. It has also been suggested that CA-interacting host factors, such as CypA and CPSF6, could modulate the cytoplasmic exposure of HIV-1 DNA to cGAS or other cytoplasmic DNA receptors. We are investigating the coordination between HIV-1 reverse transcription and uncoating in minimizing exposure of vDNA to sensors such as cGAS. Preliminary results indicate that CypA is required for both the efficient completion of reverse transcription and transport through the NPC.
哺乳动物基因组编码特异性参与核酸识别的多种病原体识别受体(PRR)。识别传感器并破译遵循核酸检测的先天免疫反应的机制的努力在很大程度上围绕研究病毒和哺乳动物细胞的相互作用而旋转。病毒在宿主细胞中复制其基因组,必须避免通过宿主细胞检测其核酸。慢病毒HIV-1也不例外。 HIV-1将其ssRNA基因组转化为一个线性dsDNA,在病毒素蛋白的复合物中,促进了vDNA进入宿主核中,并将其集成到宿主基因组中。进入宿主细胞后,HIV-1基因组RNA被主要由Ca组成的核心包围。在将HIV-1核进口到核中之前,它似乎在称为脱涂的过程中至少放出了其CA分子的一部分。图片中包含的dsDNA被认为是必需的,以使其参与并通过主机NPC。 HIV-1脱涂层的确切机制和动力学尚不清楚。有证据表明,HIV-1在完成NPC的逆转录和对接后取消了毛病,这表明逆转录和脱涂层紧密耦合。正是在不涂层过程中,HIV-1逆转录产物将容易受到宿主细胞先天信号机制感测。因此,有助于艾滋病毒脱落的病毒和宿主因素特别感兴趣。 HIV-1感染期间CA损失的机制似乎是一个受调节的过程。 CA中的某些突变已被证明对核心的总体稳定性产生负面影响,并被认为会导致过早脱落。此外,CA变体可以增强或降低核心逆转录的稳定性,从而加强了逆转录和解涂的想法紧密耦合。尽管脱膜与细胞中先天免疫反应的诱导尚未直接相关,但几项研究暗示了Ca。发现逆转录病毒限制因子TRIM5响应于HIV-1 Ca的感应,启动了MAP激酶和NF-KB信号传导。在树突状细胞中的研究表明,新合成的HIV-1 CA在刺激IFN反应中起作用。已显示来自其他病毒的衣壳蛋白在预防I型IFN诱导中起作用。单纯疱疹病毒capsid的降解导致巨噬细胞检测病毒DNA。此外,显示MLV糖基化的GAG蛋白可增强病毒核的稳定性并防止通过宿主胞质传感器检测病毒逆转录产物。有证据表明,HIV-1逆转录产物能够在感染过程中触发先天免疫反应,并且可以合理地预测HIV-1 CA可以防止在脱落之前检测病毒DNA。 DNA 3'修复外切核酸酶1(TREX1)缺乏缺乏的细胞会对HIV-1感染产生高水平的I型IFN,这表明病毒DNA产物可以刺激免疫反应,如果这种外核酸酶未降解。此外,最近的一项研究确定环状-GMP-AMP合酶(CGA)是HIV-1 DNA传感器,其激活导致I型IFN诱导。还建议CA相互作用的宿主因子(例如CYPA和CPSF6)可以调节HIV-1 DNA对CGA或其他细胞质DNA受体的细胞质暴露。我们正在研究HIV-1逆转录和不涂层之间的协调,以最大程度地减少VDNA对CGA等传感器的暴露。初步结果表明,有效地完成逆转录和通过NPC的运输是必需的。
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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vineet n kewalramani其他文献
vineet n kewalramani的其他文献
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7338599 - 财政年份:
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$ 13.42万 - 项目类别:
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$ 13.42万 - 项目类别:
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