Regulatory Crosstalk Between Human Endogenous Retroviruses, HIV, and EBV, in Lymphoma
淋巴瘤中人内源性逆转录病毒、HIV 和 EBV 之间的监管串扰
基本信息
- 批准号:10616708
- 负责人:
- 金额:$ 117.81万
- 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:2021-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AIDS related cancerAIDS-Related Diffuse Large B-cell LymphomaAcquired Immunodeficiency SyndromeAffectB-Cell LymphomasB-LymphocytesBCL2 geneBCL6 geneBindingBiologyBrazilCD4 Positive T LymphocytesCell LineCell ProliferationCellsClear cell renal cell carcinomaCoculture TechniquesCommon NeoplasmComplexCytotoxic T-LymphocytesDNADNA Transposable ElementsDataDeveloped CountriesDevelopmentDiseaseElementsEndogenous RetrovirusesEnhancersEnvironmental Risk FactorEpitopesEpstein-Barr Virus InfectionsEvolutionFamilyGene ExpressionGenesGeneticGenomicsGrantHIVHIV InfectionsHIV SeronegativityHumanHuman CloningHuman GenomeHuman Herpesvirus 4Immune TargetingImmunologyImmunophenotypingImmunotherapyIn VitroIncidenceIndividualInfectionJunk DNAK-18 conjugateLinkLymphomaLymphoma cellLymphomagenesisMalignant NeoplasmsMediatingMedicineMolecularMorphologyNucleic AcidsOncogenicPathogenesisPathologicPatientsPatternPersonsPhysiologicalPhysiologyPlayProcessProspective cohortProteinsProto-OncogenesRegulationRepressionRetrospective cohortRetroviridaeRoleSamplingSpecialistStandardizationSystemT-LymphocyteT-Lymphocyte EpitopesTestingTherapeutic InterventionTissuesTonsilTranslatingTumor SubtypeTumor Suppressor GenesUnited StatesUntranslated RNAUp-RegulationViralViral GenomeViremiaVirusWorkcomputerized toolsexomein vitro Modelinfected B celllarge cell Diffuse non-Hodgkin&aposs lymphomalymph nodesneoplastic cellnew therapeutic targetperipheral bloodpromoterresponseribosome profilingsingle-cell RNA sequencingsynergismtargeted treatmenttranscriptome sequencingtranscriptomicstumortumor microenvironmenttumor progressiontumorigenesis
项目摘要
PROJECT SUMMARY/ABSTRACT
Approximately 8% of the human genome is composed of sequences directly derived from germline infections of
diverse retroviruses, which have accumulated over the past ~100 million years of mammalian evolution. None
of these human endogenous retroviruses (HERVs) are known to represent fully functional retroviruses, but most
have retained noncoding regulatory sequences that can control expression of cellular genes acting as promoters
or enhancers, and some still encode proteins with various functional activities. While HERV sequences are often
ignored as merely inconsequential ‘junk’ DNA, there is evidence that a subset of these elements play crucial
roles in human physiology and disease, including cancer. Our previous work, as well as that of others, have
shown that both HIV and EBV infections activate certain HERV families that have oncogenic activities, and our
preliminary data reveal an overlap between these elements. Given that diffuse large B cell lymphomas (DBCL)
are frequently associated with EBV infection in people living with HIV, we hypothesize that there is a complex
intercellular regulatory crosstalk between AIDS related (AR)-DLBCL, HIV-infected T cells and the tissue
microenvironment, that is in part mediated by a specific subset of HERVs and their derived products that are
synergistically activated and promote oncogenesis. We will study DLBCL obtained from patients with or without
EBV (and with or without HIV) from the USA and Brazil, which will be comprehensively characterized
pathologically and molecularly using single-cell genomics and spatial transcriptomics. We will analyze these data
using computational tools we have tailored to profile and link HERV and gene expression. Furthermore, we will
establish in vitro models to dissect with precision the functional impact of HERV on the crosstalk between T cells
infected by HIV and B cells with or without EBV. We will also determine if differential HERV expression creates
neoantigenic epitopes, a feature that can be exploited for immunotherapy. This will be accomplished through
three specific aims: 1) Characterize and profile HERV regulation and expression within single cells in DLBCL
and AR-DLBCL; 2) Establish in vitro models to dissect the interaction between cellular and endogenous and
exogenous viruses in AR-DLBCL; 3) Identification of neo-antigenic HERV epitopes in DLBCL and ascertain if
cloned HERV specific CTL can lyse lymphoma cells in vitro. Our team consists of specialists in lymphoma biology
and medicine, transposable elements and HERVs, HIV and EBV viral immunology. Together, we will generate
understandings of how HERVs contribute to the pathogenesis of AR-DLCBL, and identify new antigenic targets
for novel therapies.
项目总结/摘要
大约8%的人类基因组由直接来源于生殖系感染的序列组成。
不同的逆转录病毒,在过去的约1亿年的哺乳动物进化中积累。没有一
已知这些人内源性逆转录病毒(HERV)中的一种代表全功能逆转录病毒,但大多数
保留了非编码调节序列,这些序列可以作为启动子控制细胞基因的表达
或增强子,并且一些仍然编码具有各种功能活性的蛋白质。虽然HERV序列通常
尽管被忽视为无关紧要的“垃圾”DNA,但有证据表明这些元素的一个子集发挥着至关重要的作用
在人类生理和疾病中的作用,包括癌症。我们以前的工作,以及其他人的工作,
表明HIV和EBV感染都激活了某些具有致癌活性的HERV家族,
初步数据显示,这些要素之间存在重叠。鉴于弥漫性大B细胞淋巴瘤(DBCL)
经常与HIV感染者的EBV感染有关,我们假设存在一种复杂的
AIDS相关(AR)-DLBCL、HIV感染的T细胞和组织之间的细胞间调节串扰
微环境,部分由HERV及其衍生产物的特定子集介导,
协同激活并促进肿瘤发生。我们将研究从患有或不患有DLBCL的患者中获得的DLBCL,
来自美国和巴西的EB病毒(以及是否携带艾滋病毒),将对其进行全面表征
在病理学和分子学上使用单细胞基因组学和空间转录组学。我们将分析这些数据
使用计算工具,我们已经定制了HERV和基因表达的概况和联系。此外,我们将
建立体外模型,以精确分析HERV对T细胞间串扰的功能影响
感染HIV和B细胞,有或没有EBV。我们还将确定差异HERV表达是否产生
新抗原表位,这是一个可以用于免疫治疗的特征。这将通过以下方式实现:
三个具体目标:1)表征和分析DLBCL中单个细胞内HERV的调控和表达
和AR-DLBCL; 2)建立体外模型以剖析细胞和内源性之间的相互作用,
AR-DLBCL中的外源病毒; 3)DLBCL中新抗原HERV表位的鉴定,并确定
克隆的HERV特异性CTL在体外可裂解淋巴瘤细胞。我们的团队由淋巴瘤生物学专家组成
转座因子和HERV,HIV和EBV病毒免疫学。我们将共同创造
理解HERV如何促进AR-DLCBL的发病机制,并确定新的抗原靶点
新的治疗方法。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ribosomal profiling of human endogenous retroviruses in healthy tissues.
- DOI:10.1186/s12864-023-09909-x
- 发表时间:2024-01-02
- 期刊:
- 影响因子:4.4
- 作者:Dopkins, Nicholas;Singh, Bhavya;Michael, Stephanie;Zhang, Panpan;Marston, Jez L.;Fei, Tongyi;Singh, Manvendra;Feschotte, Cedric;Collins, Nicholas;Bendall, Matthew L.;Nixon, Douglas F.
- 通讯作者:Nixon, Douglas F.
3D chromosomal architecture in germinal center B cells and its alterations in lymphomagenesis.
- DOI:10.1016/j.gde.2022.101915
- 发表时间:2022-06
- 期刊:
- 影响因子:4
- 作者:Papin, Antonin;Cesarman, Ethel;Melnick, Ari
- 通讯作者:Melnick, Ari
Endogenous Reverse Transcriptase Inhibition Attenuates TLR5-Mediated Inflammation.
- DOI:10.1128/mbio.03280-22
- 发表时间:2023-02-28
- 期刊:
- 影响因子:6.4
- 作者:
- 通讯作者:
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ETHEL CESARMAN其他文献
ETHEL CESARMAN的其他文献
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{{ truncateString('ETHEL CESARMAN', 18)}}的其他基金
Tri-I Stimulating Access to Research in Residency program (Tri-I StARR - NIAID)
Tri-I 促进住院医师研究项目 (Tri-I StARR - NIAID)
- 批准号:
10592130 - 财政年份:2023
- 资助金额:
$ 117.81万 - 项目类别:
Rapid Sample-to-Answer Diagnosis of Kaposi's Sarcoma Across Sub-Saharan Africa using KS-COMPLETE
使用 KS-COMPLETE 对撒哈拉以南非洲地区的卡波西肉瘤进行快速样本到答案诊断
- 批准号:
10416778 - 财政年份:2022
- 资助金额:
$ 117.81万 - 项目类别:
Rapid Sample-to-Answer Diagnosis of Kaposi's Sarcoma Across Sub-Saharan Africa using KS-COMPLETE
使用 KS-COMPLETE 对撒哈拉以南非洲地区的卡波西肉瘤进行快速样本到答案诊断
- 批准号:
10642906 - 财政年份:2022
- 资助金额:
$ 117.81万 - 项目类别:
Regulatory Crosstalk Between Human Endogenous Retroviruses, HIV, and EBV, in Lymphoma
淋巴瘤中人内源性逆转录病毒、HIV 和 EBV 之间的监管串扰
- 批准号:
10228431 - 财政年份:2021
- 资助金额:
$ 117.81万 - 项目类别:
Regulatory Crosstalk Between Human Endogenous Retroviruses, HIV, and EBV, in Lymphoma
淋巴瘤中人内源性逆转录病毒、HIV 和 EBV 之间的监管串扰
- 批准号:
10398963 - 财政年份:2021
- 资助金额:
$ 117.81万 - 项目类别:
(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment
(PQ 6) KSHV 肿瘤发生和 KS 免疫环境的新模型
- 批准号:
10737765 - 财政年份:2020
- 资助金额:
$ 117.81万 - 项目类别:
(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment
(PQ 6) KSHV 肿瘤发生和 KS 免疫环境的新模型
- 批准号:
10397107 - 财政年份:2020
- 资助金额:
$ 117.81万 - 项目类别:














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