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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.

项目总结/文摘

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.