The role of POM121 in HIV-1 infection

POM121 在 HIV-1 感染中的作用

• 批准号: 10926217
• 负责人: vineet n kewalramani
• 金额: $ 29.58万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926217
• 关键词: Affect; Antiviral Therapy; Biology; Capsid; Cells; Chimeric Proteins; Chromatin; Cyclophilin A; Gene Transduction Agent; Genome; HIV-1; Infection; Integration Host Factors; Lentivirus Vector; Maps; Mediating; Nuclear; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Play; Process; Protein Analysis; Protein Isoforms; Proteins; Regulation; Role; Surface; TRIM5 gene; Virus; anti-cancer; chimeric antigen receptor T cells; gene therapy; improved; migration

The HIV-1 core, composed as a lattice of CA hexamers and pentamers, engages FG-nucleoporins to enable transport of the virus through nuclear pore complexes to access host cell chromatin. The choreography of this interaction, specifically which nucleoporins are engaged in what order, and the multivalency of this interaction, specifically which interactions are overlapping and which might be displaced, are key issues that need to be resolved to better understand the mechanism of HIV-1 nuclear entry. HIV-1 CA mediates these interactions and is highly vulnerable to antiviral therapy because of the central role that CA plays in engaging possibly a dozen or more host factors through the same interface. How HIV-1 migrates through the nuclear pore complex also affects where it integrates its genome in host cell chromatin. Given the use of HIV-1 derived lentiviral vectors in gene therapy, including the establishment of anticancer CAR T cells, the elucidation of this biology could be beneficial in developing improved vectors for gene therapy. The interaction of HIV-1 CA with POM121 appears to be one of the strongest ones in the cell based on TRIM5 fusion protein analysis. We thus want to define more precisely the interaction surfaces. Based on the subcellular localization of POM121, we expect this interaction to be early in the nuclear entry process. This is also consistent with regulation by CypA. We will use the domain interaction studies as a basis to help understand how CypA governs use of POM121 and what role POM121 plays in HIV-1 migration through the nuclear pore complex. Finally, there are other isoforms of POM121 - POM121C and soluble POM121. We are examining whether they affect HIV-1 infection and whether conserved domains are contributing to interactions with HIV-1 CA.

HIV-1核心作为Ca六聚体和五聚体的晶格组成，使FG核核蛋白可以通过核孔复合物将病毒运输，从而进入宿主细胞染色质。这种相互作用的编舞，特别是哪种核孔蛋白以什么顺序参与，这种相互作用的多价，特别是哪些相互作用是重叠的，可能是哪些相互作用，是需要解决的关键问题，以更好地了解HIV-1核进入的机制。 HIV-1 CA介导了这些相互作用，并且高度容易受到抗病毒疗法的影响，因为CA在通过相同的界面中可能吸引了十几个或更多宿主因素。 HIV-1如何通过核孔复合物迁移也会影响其在宿主细胞染色质中整合基因组的位置。考虑到HIV-1衍生的慢病毒载体在基因治疗中，包括建立抗癌CAR T细胞，因此阐明该生物学可能有益于开发改善基因治疗的载体。基于TRIM5融合蛋白分析，HIV-1 CA与POM121的相互作用似乎是细胞中最强的相互作用之一。因此，我们想更精确地定义相互作用表面。基于POM121的亚细胞定位，我们预计这种相互作用在核进入过程中会很早。这也与CYPA的调节一致。我们将使用域相互作用研究作为基础，以帮助了解CYPA如何控制POM121的使用以及POM121在HIV-1通过核孔复合体中扮演什么作用。最后，还有POM121 -POM121C和可溶性POM121的其他同工型。我们正在研究它们是否影响HIV-1感染以及保守的领域是否有助于与HIV-1 CA的相互作用。

项目成果

Co-transcriptional production of RNA-DNA hybrids for simultaneous release of multiple split functionalities.

• DOI: 10.1093/nar/gkt1001
• 发表时间: 2014-02
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Afonin KA;Desai R;Viard M;Kireeva ML;Bindewald E;Case CL;Maciag AE;Kasprzak WK;Kim T;Sappe A;Stepler M;Kewalramani VN;Kashlev M;Blumenthal R;Shapiro BA
• 通讯作者: Shapiro BA

Triggering of RNA interference with RNA-RNA, RNA-DNA, and DNA-RNA nanoparticles.

• DOI: 10.1021/nn504508s
• 发表时间: 2015-01-27
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Afonin, Kirill A.;Viard, Mathias;Kagiampakis, Ioannis;Case, Christopher L.;Dobrovolskaia, Marina A.;Hofmann, Jen;Vrzak, Ashlee;Kireeva, Maria;Kasprzak, Wojciech K.;KewalRamani, Vineet N.;Shapiro, Bruce A.
• 通讯作者: Shapiro, Bruce A.