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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：
ETHEL CESARMAN
金额：
$ 117.81万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
https://reporter.nih.gov/project-details/10616708
关键词：
AIDS related cancer AIDS-Related Diffuse Large B-cell Lymphoma Acquired Immunodeficiency Syndrome Affect B-Cell Lymphomas B-Lymphocytes BCL2 gene BCL6 gene Binding Biology Brazil CD4 Positive T Lymphocytes Cell Line Cell Proliferation Cells Clear cell renal cell carcinoma Coculture Techniques Common Neoplasm Complex Cytotoxic T-Lymphocytes DNA DNA Transposable Elements Data Developed Countries Development Disease Elements Endogenous Retroviruses Enhancers Environmental Risk Factor Epitopes Epstein-Barr Virus Infections Evolution Family Gene Expression Genes Genetic Genomics Grant HIV HIV Infections HIV Seronegativity Human Human Cloning Human Genome Human Herpesvirus 4 Immune Targeting Immunology Immunophenotyping Immunotherapy In Vitro Incidence Individual Infection Junk DNA K-18 conjugate Link Lymphoma Lymphoma cell Lymphomagenesis Malignant Neoplasms Mediating Medicine Molecular Morphology Nucleic Acids Oncogenic Pathogenesis Pathologic Patients Pattern Persons Physiological Physiology Play Process Prospective cohort Proteins Proto-Oncogenes Regulation Repression Retrospective cohort Retroviridae Role Sampling Specialist Standardization System T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic Intervention Tissues Tonsil Translating Tumor Subtype Tumor Suppressor Genes United States Untranslated RNA Up-Regulation Viral Viral Genome Viremia Virus Work computerized tools exome in vitro Model infected B cell large cell Diffuse non-Hodgkin&apos s lymphoma lymph nodes neoplastic cell new therapeutic target peripheral blood promoter response ribosome profiling single-cell RNA sequencing synergism targeted treatment transcriptome sequencing transcriptomics tumor tumor microenvironment tumor progression tumorigenesis

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.

项目概要/摘要大约 8% 的人类基因组由直接源自生殖系感染的序列组成多种逆转录病毒，在过去约一亿年的哺乳动物进化中积累。没有任何已知这些人类内源性逆转录病毒 (HERV) 代表了功能齐全的逆转录病毒，但大多数保留了非编码调控序列，可以作为启动子控制细胞基因的表达或增强子，有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起着至关重要的作用在人类生理和疾病（包括癌症）中的作用。我们之前的工作以及其他人的工作已经研究表明，HIV 和 EBV 感染都会激活某些具有致癌活性的 HERV 家族，我们的研究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 感染相关，我们假设存在一个复杂的因素艾滋病相关 (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，部分是由 HERV 的特定子集及其衍生产品介导的协同激活并促进肿瘤发生。我们将研究从有或没有患有 DLBCL 的患者身上获得的 DLBCL。来自美国和巴西的 EBV（以及带有或不带有 HIV），将对其进行全面表征使用单细胞基因组学和空间转录组学进行病理学和分子学研究。我们将分析这些数据使用我们定制的计算工具来分析和关联 HERV 和基因表达。此外，我们将建立体外模型，精确剖析 HERV 对 T 细胞间串扰的功能影响被 HIV 和 B 细胞感染，有或没有 EBV。我们还将确定差异 HERV 表达是否会产生新抗原表位，一种可用于免疫治疗的特征。这将通过以下方式完成三个具体目标：1) 表征和分析 DLBCL 单细胞内 HERV 的调控和表达和 AR-DLBCL； 2）建立体外模型来剖析细胞与内源性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 表位的鉴定并确定是否克隆的HERV特异性CTL可以在体外裂解淋巴瘤细胞。我们的团队由淋巴瘤生物学专家组成以及医学、转座因子和 HERV、HIV 和 EBV 病毒免疫学。我们将共同创造了解 HERV 如何促进 AR-DLCBL 的发病机制，并确定新的抗原靶点用于新疗法。

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：
BMC GENOMICS
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.