T-cell Transformation by Oncoviruses

肿瘤病毒对 T 细胞的转化

基本信息

项目摘要

In this project we have two main approaches: Approach 1: To integrate information obtained by functional biochemical studies to infectivity and persistence of HTLV-1 in dendritic cells and T-cells in vitro. Approach 2: To verify the role of orf I and orf II in viral persistence in animal models. The viral genome encodes mRNAs for several non-structural proteins that affect cellular pathways and modulate viral replication. One such protein, p12, encoded by orf I, localizes to the ER and Golgi and cellular membranes. The proteolytic cleavage of p12 dictates its cellular localization and functions. The removal of a non-canonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12 is necessary for trafficking to the Golgi apparatus and the generation of a completely cleaved 8 kDa protein. The 8 kDa protein traffics to the cell surface, is recruited to the immunological synapse following T-cell receptor (TCR) ligation, down-regulates TCR proximal signaling and increases viral transmission. The full length form of p12 resides in the ER and interacts with the beta and gamma-c chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1-infected patients reveals frequent amino acid substitutions within orf-I that inhibit proteolytic cleavage, suggesting that ER associated functions of p12I may be selected in vivo. Because HTLV-I orf-I is important for viral transmission and persistence, we sought to determine the genetic variation of p12 protein in HTLV-1 infected individuals and investigate a possible association between p12 mutations, its cleavage status, proviral load, and disease outcome. In this study, we performed reverse genetics of 160 patients to identify mutations in orf-I. We found that individuals that harbor clones expressing both p12 and p8 have higher virus loads compared to individuals that harbor clones expressing predominantly p12 or predominantly p8. Further, we constructed infectious molecular clones expressing distinct orf-I isoforms (p12/p8;p12;p8). Clonal cell lines were established, characterized and used in a rhesus macaque model. Results from these studies clearly demonstrate that viral persistence requires expression of both p12 and p8 isoforms. Importantly, our results suggest that p12/p8 expression impacts CTL escape.We also analyzed the role of in p12 and p8 function. We found that HTLV-1 p12 and p8 form disulfide-linked homo-and heterodimers and that the monomeric forms of these proteins are palmitoylated. Mutation of cysteine 39 within these proteins disrupted dimerization and palmitoylation of both p12 and p8 without affecting protein localization. These studies suggest palmitoylation of p8 dirupts dimer formation and targets the monomeric form to modulate cell signaling pathways to increase cell-to-cell adhesion and viral infectivity. Determining the mechanism by which p12 and p8 dimerization and functions are regulated would advance our understanding of HTLV-1 pathogenesis and could identify potential novel therapeutic targets for the treatment of HTLV-1-infected individuals.
在这个项目中,我们有两个主要的方法:方法1:整合功能生化研究所获得的信息,在体外树突状细胞和T细胞中的HTLV-1的感染性和持久性。方法2:在动物模型中验证orf I和orf II在病毒持久性中的作用。 病毒基因组编码影响细胞途径和调节病毒复制的几种非结构蛋白的mRNA。其中一种蛋白质p12由orf I编码,定位于ER、高尔基体和细胞膜。p12的蛋白水解切割决定了其细胞定位和功能。在p12的氨基末端内去除非典型内质网(ER)保留/检索信号对于运输到高尔基体和产生完全切割的8 kDa蛋白是必要的。8 kDa蛋白质运输至细胞表面,在T细胞受体(TCR)连接后被募集至免疫突触,下调TCR近端信号传导并增加病毒传播。p12的全长形式存在于ER中,并与白细胞介素-2受体(IL-2 R)的β和γ-c链、I类主要组织相容性复合体(MHC)的重链以及钙网蛋白和钙连接蛋白相互作用。HTLV-1感染患者的离体样本的ORF-I的遗传分析揭示了ORF-I内抑制蛋白水解裂解的频繁氨基酸取代,表明ER相关的p12 I功能可以在体内选择。由于HTLV-1 orf-1对病毒传播和持久性很重要,我们试图确定HTLV-1感染个体中p12蛋白的遗传变异,并研究p12突变、其裂解状态、前病毒载量和疾病结局之间的可能关联。在这项研究中,我们对160名患者进行了反向遗传学研究,以确定orf-I的突变。我们发现,与主要表达p12或主要表达p8的克隆相比,携带p12和p8的克隆的个体具有更高的病毒载量。此外,我们构建了感染性的分子克隆表达不同的orf-I亚型(p12/p8;p12;p8)。建立克隆细胞系,表征并用于恒河猴模型。这些研究的结果清楚地表明,病毒的持久性需要p12和p8亚型的表达。重要的是,我们的结果表明p12/p8表达影响CTL逃逸,我们还分析了p12和p8在CTL逃逸中的作用。我们发现HTLV-1 p12和p8形成二硫键连接的同源和异源二聚体,并且这些蛋白质的单体形式被棕榈酰化。这些蛋白质内的半胱氨酸39的突变破坏了p12和p8的二聚化和棕榈酰化,而不影响蛋白质定位。这些研究表明p8的棕榈酰化破坏了二聚体的形成,并靶向单体形式来调节细胞信号传导途径,以增加细胞间粘附和病毒感染性。确定p12和p8二聚化和功能调节的机制将促进我们对HTLV-1发病机制的理解,并可以确定治疗HTLV-1感染个体的潜在新治疗靶点。

项目成果

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Genoveffa Franchini其他文献

Genoveffa Franchini的其他文献

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{{ truncateString('Genoveffa Franchini', 18)}}的其他基金

INDUCTION OF SIV-SPECIFIC CD8+ LYMPHOCYTES
SIV 特异性 CD8 淋巴细胞的诱导
  • 批准号:
    6970744
  • 财政年份:
    2004
  • 资助金额:
    $ 178.06万
  • 项目类别:
INDUCTION OF SIV-SPECIFIC CD8+ INTRAEPITHELIAL LYMPHOCYTES
SIV 特异性 CD8 上皮内淋巴细胞的诱导
  • 批准号:
    6939813
  • 财政年份:
    2003
  • 资助金额:
    $ 178.06万
  • 项目类别:
VACCINE STRATEGIES FOR INDUCTION OF ANTI-HIV MUCOSAL IMMUNE RESPONSES
诱导抗 HIV 粘膜免疫反应的疫苗策略
  • 批准号:
    6939800
  • 财政年份:
    2003
  • 资助金额:
    $ 178.06万
  • 项目类别:
DEVELOPMENT OF AN HIV-1 AND HTLV-1 VACCINE IN ANIMAL MODELS
在动物模型中开发 HIV-1 和 HTLV-1 疫苗
  • 批准号:
    2463673
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:
Vaccine Modalities to Prevent HIV-I Infection
预防 HIV-I 感染的疫苗方式
  • 批准号:
    6950125
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:
Combination of Vaccine Modalities to Prevent HIV-I Infec
预防 HIV-1 感染的疫苗方式组合
  • 批准号:
    7038625
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:
T-cell Transformation by Oncoviruses
肿瘤病毒对 T 细胞的转化
  • 批准号:
    7337917
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:
Preventive Vaccines for HIV
艾滋病毒预防疫苗
  • 批准号:
    8349347
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:
Combination of Vaccine Modalities to Prevent HIV-I Infec
预防 HIV-1 感染的疫苗方式组合
  • 批准号:
    6761611
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:
Role of the HTLV-1A and HTLV1-C inflammatory profile in disease
HTLV-1A 和 HTLV1-C 炎症谱在疾病中的作用
  • 批准号:
    10014283
  • 财政年份:
  • 资助金额:
    $ 178.06万
  • 项目类别:

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