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
• 负责人: ETHEL CESARMAN
• 金额: $ 117.86万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10398963
• 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; Human immunodeficiency virus test; Immune Targeting; Immunology; 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; 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' s lymphoma; lymph nodes; neoplastic cell; new therapeutic target; peripheral blood; promoter; response; ribosome profiling; single-cell RNA sequencing; targeted treatment; transcriptome sequencing; transcriptomics; tumor; tumor microenvironment; tumor progression; tumorigenesis

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.

项目摘要/摘要 大约8％的人类基因组由直接衍生自生殖感染的序列组成 在过去的约1亿年的哺乳动物进化中积累的潜水病毒逆转录病毒。没有任何 已知这些人内源性逆转录病毒（HERV）代表功能齐全的逆转录病毒，但大多数 保留了非编码调节序列，可以控制用作启动子的细胞基因的表达 或增强剂，有些仍然用各种功能活动编码蛋白质。虽然赫夫序列通常是 被忽略只是无关紧要的“垃圾” DNA，有证据表明这些元素的子集发挥了关键 在包括癌症在内的人类生理和疾病中的作用。我们以前的工作以及他人的工作 表明艾滋病毒和EBV感染激活了某些具有致癌活动的HERV家族，我们 初步数据揭示了这些元素之间的重叠。鉴于扩散的大B细胞淋巴瘤（DBCL） 在艾滋病毒感染者中经常与EBV感染有关，我们假设有一个复杂的 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，部分是由特定的HERV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的患者获得的DLBCL 来自美国和巴西的EBV（以及有或没有艾滋病毒），这将是全面的特征 我们将分析这些数据 使用计算工具，我们定制了用于轮廓和链接HERV和基因表达的。此外，我们会的 建立体外模型，以精确地解剖HERV对T细胞之间串扰的功能影响 由或没有EBV的HIV和B细胞感染。我们还将确定差异HERV表达是否会产生 新抗原的表位，可以探索用于免疫疗法的特征。这将通过 三个具体目的：1）在DLBCL中的单个细胞中表征和概况的HERV调节和表达 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）鉴定DLBCL中的新抗原herv表位并确定是否确定 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，可转座元素和HERV，HIV和EBV病毒免疫学。在一起，我们将生成 对HERV如何促进AR-DLCBL的发病机理的理解，并确定新的抗原靶标 用于新型疗法。