Characterization of the antiviral immunity factor CD317/tetherin

抗病毒免疫因子 CD317/tetherin 的表征

• 批准号: 163617427
• 负责人: Professor Dr. Oliver T. Fackler, Ph.D.
• 金额: --
• 依托单位: Max-von-Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/163617427?language=en
• 关键词: Characterization; antiviral; immunity; factor; CD317

Mammals have evolved a set of intrinsic cellular defense mechanisms capable of inhibiting the replication of viral pathogens. These restriction factors (RFs), which can be constitutively expressed but are frequently up-regulated by host cells in response to virus infection, impose particularly effective barriers in the context of cross-species transmission of viruses. The focus of this project is on the host RF CD317 (also referred to as BST-2/HM1.24/tetherin) that acts late in the HIV replication cycle by potently blocking the release of mature HIV-1 particles from productively infected cells. The activity of CD317 can be antagonized by the HIV-1 protein Vpu and the overall goal of this project is to define the molecular mechanisms of CD317-mediated restriction and its antagonism by HIV-1 Vpu. Our results of the first funding period together with those by other laboratories established that Vpu antagonizes the particle release restriction imposed by CD317 via two mechanisms: (i) impairing overall delivery to the host cell plasma membrane and (ii) altering the submembrane lateral distribution within the plasma membrane for exclusion from viral budding sites. While Vpu helix 2 emerges as a determinant for both Vpu effects, the highly conserved phospho-di-serine motif of Vpu is only involved in the inhibition of CD317 anterograde transport and recycling. In additional preliminary work we identified the host cell protein Arl6IP1 as novel Vpu interactor that enhances the CD317-mediated restriction and established a whole body-tissue microarray-based expression profiling approach to define in situ expression patterns of relevant host factors at physiological sites of HIV transmission. Building on these findings the main goals of the second funding period are (i) the dissection of the molecular mechanisms and host cell ligands employed by Vpu to affect intracellular transport and membrane segregation of CD317, (ii) characterization of the role of the newly identified cellular Vpu interactor Arl6IP1 in HIV-1 restriction, and (iii) the identification of physiologically relevant sites of CD317-and Arl6IP1-mediated restriction ex vivo and in vivo. To address these cardinal questions we will integrate biochemistry, intracellular transport, super-resolution microscopy, virology and immunohistology approaches in the context of the well-established collaboration between our two laboratories. Results of these studies are expected to significantly advance our understanding by which molecular mechanisms and at which physiological sites the interplay between HIV-1 Vpu and CD317 shape HIV-1 pathogenesis.

哺乳动物已经进化出一套能够抑制病毒病原体复制的内在细胞防御机制。这些限制性因子（RF）可以组成型表达，但在病毒感染时经常被宿主细胞上调，在病毒跨物种传播的背景下施加特别有效的屏障。该项目的重点是宿主RF CD 317（也称为BST-2/HM 1.24/tetherin），它通过有效阻止成熟HIV-1颗粒从生产性感染细胞中释放而在HIV复制周期后期发挥作用。CD 317的活性可以被HIV-1蛋白Vpu拮抗，本项目的总体目标是确定CD 317介导的限制性酶切的分子机制以及HIV-1 Vpu对其的拮抗作用。我们的第一个资助期的结果以及其他实验室的结果确定，Vpu通过两种机制拮抗CD 317施加的颗粒释放限制：（i）损害向宿主细胞质膜的总体递送和（ii）改变质膜内的膜下横向分布，以排除病毒出芽位点。虽然Vpu螺旋2作为Vpu效应的决定因素出现，但Vpu的高度保守的磷酸二丝氨酸基序仅参与抑制CD 317的顺行转运和再循环。在额外的初步工作中，我们确定了宿主细胞蛋白Arl 6 IP 1作为新的Vpu相互作用，增强了CD 317介导的限制，并建立了一个整体组织微阵列为基础的表达谱的方法来定义在原位表达模式的相关宿主因子在HIV传播的生理位点。基于这些发现，第二个资助期的主要目标是（i）分析Vpu影响CD 317的细胞内转运和膜分离的分子机制和宿主细胞配体，（ii）表征新鉴定的细胞Vpu相互作用物Ar 16 IP 1在HIV-1限制中的作用，和（iii）离体和体内鉴定CD 317和Ar 16 IP 1介导的限制的生理学相关位点。为了解决这些基本问题，我们将整合生物化学，细胞内运输，超分辨率显微镜，病毒学和免疫组织学方法在我们两个实验室之间的良好合作的背景下。这些研究的结果有望显着推进我们的理解，通过哪些分子机制和在哪些生理位点之间的相互作用HIV-1 Vpu和CD 317形状HIV-1的发病机制。

项目成果

HIV-1 Vpu Antagonizes CD317/Tetherin by Adaptor Protein-1-Mediated Exclusion from Virus Assembly Sites

HIV-1 Vpu 通过接头蛋白 1 介导的病毒组装位点排斥来拮抗 CD317/Tetherin

• DOI: 10.1128/jvi.00504-16
• 发表时间: 2016
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Pujol FM;Laketa V;Schmidt F;Mukenhirn M;Müller B;Boulant S;Grimm D;Keppler OT;Fackler OT
• 通讯作者: Fackler OT

HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins

• DOI: 10.1128/jvi.02333-14
• 发表时间: 2014-12-01
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Haller, Claudia;Mueller, Birthe;Fackler, Oliver T.
• 通讯作者: Fackler, Oliver T.

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia

• DOI: 10.1038/nm.4255
• 发表时间: 2017-02-01
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Schneider, Constanze;Oellerich, Thomas;Cinatl, Jindrich, Jr.
• 通讯作者: Cinatl, Jindrich, Jr.

In vivo expression profile of the antiviral restriction factor and tumor-targeting antigen CD317/BST-2/HM1.24/tetherin in humans

• DOI: 10.1073/pnas.1101684108
• 发表时间: 2011-08-16
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Erikson, Elina;Adam, Tarek;Keppler, Oliver T.
• 通讯作者: Keppler, Oliver T.

SAMHD1's protein expression profile in humans

• DOI: 10.1189/jlb.4hi0714-338rr
• 发表时间: 2015-02
• 期刊: Journal of Leukocyte Biology
• 影响因子: 5.5
• 作者: Sarah Schmidt;Kristína Schenková;T. Adam;Elina Erikson;Judith Lehmann‐Koch;S. Sertel;B. Verhasselt;O. Fackler;F. Lasitschka;O. Keppler