HIV-driven B cell activation: role in the genesis of AIDS-related lymphoma

HIV 驱动的 B 细胞激活：在 AIDS 相关淋巴瘤发生中的作用

基本信息

批准号：
8467219
负责人：
OTONIEL MARTINEZ-MAZA
金额：
$ 31.96万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467219
关键词：
AIDS related cancer AIDS-Related Lymphoma AIDS-Related Non-Hodgkin&apos s Lymphoma Accounting Acquired Immunodeficiency Syndrome Anti-Retroviral Agents Antibodies Automobile Driving B-Cell Activation B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes BCL1 Oncogene Biological Markers CCL17 gene CCL22 gene CD4 Positive T Lymphocytes CD40 Ligand Cause of Death Cells Characteristics Chronic DNA DNA Double Strand Break Developed Countries Development Diagnosis Disease Disease Progression Early Diagnosis Etiology Event Family Future Gene Expression Profile Genes Genetic Recombination Gut associated lymphoid tissue HIV HIV Infections HIV-1 Herpesviridae Infections Highly Active Antiretroviral Therapy Human Herpesvirus 4 Human Herpesvirus 8 IGH@ gene cluster IL6 gene Immune Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulin Variable Region In Vitro Infection Interleukin-10 Lead Lesion Lymphoma Lymphomagenesis Malignant Neoplasms Mediating MicroRNAs Mind Molecular Mutation Oncogenes Oncogenic Pathogenesis Pattern Peripheral Peripheral Blood Mononuclear Cell Persons Phenotype Plasma Play Process Production Relative (related person)Risk Risk Assessment Role Seminal Serum Source T-Cell Activation T-Lymphocyte TNFRSF5 gene TNFSF5 gene Virion Work activation-induced cytidine deaminase cell type chemokine cytokine immune function in vivo macrophage member monocyte overexpression paralogous gene prophylactic public health relevance therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Untreated HIV infection results in not only in the progressive loss of T cell immune function, but also in chronic polyclonal B cell activation. The risk for developing B cell non-Hodgkin's lymphoma also is greatly elevated in HIV+ persons. Virtually all AIDS-related lymphomas (ARL) are of B cell origin. HIV infection-associated B cell hyperactivation is believed to play a central role in the genesis of ARL, as B cell activation involves two molecular processes that can create the seminal molecular lesions seen in ARL: 1) immunoglobulin heavy chain gene (IgH) class switch recombination (CSR), a process that involves double-strand DNA breaks and recombination, and 2) somatic hypermutation (SHM), DNA hypermutation of the variable region of antibody genes. Errors in IgH CSR and SHM can lead directly to oncogene mutations and/or translocations that result in ARL. IgH CSR and SHM are both mediated by activation-induced cytidine deaminase (AICDA), a member of the APOBEC family. In our prior work, we saw that PBMC B cell AICDA expression was elevated for several years preceding the diagnosis of ARL, as were serum levels of B cell stimulatory cytokines. We also found that HIV virions carrying CD40 ligand (CD40L), a T cell-produced B cell stimulatory molecule, can drive B cell activation and AICDA expression. Given that HIV can potently induce B cell activation via host cell- encoded stimulatory molecules incorporated into virions, and that B cell activation can contribute to the development of ARL, it is important to better define the role of such virion-associated stimulatory molecules in driving B cell activation With this in mind, the specific aims of this study are to: 1) define the ability of CD40L+ HIV to promote oncogenic events in B cells, 2) define the expression of CD40L on HIV virions in vivo, throughout the course of HIV disease, and 3) determine if the development of ARL is associated with elevated expression of CD40L or other B cell-stimulatory molecules on HIV virions from plasma, as well as with a gene expression pattern in circulating T cells that is characteristic of TFH/TH17 cells, elevated serum levels of B cell- stimulatory cytokines, and/or, elevated plasma levels of EBV and/or KSHV DNA. By better defining the association of CD40L+ HIV and ARL we hope to elucidate the pathogenesis of these cancers, providing information that will inform future work on risk assessment and early detection, and on the development of therapeutics.

描述（由申请人提供）：未处理的HIV感染不仅会导致T细胞免疫功能的进行性丧失，还导致慢性多克隆B细胞激活。在HIV+患者中，患B细胞非霍奇金淋巴瘤的风险也大大升高。几乎所有与AIDS相关的淋巴瘤（ARL）都是B细胞起源的。 HIV infection-associated B cell hyperactivation is believed to play a central role in the genesis of ARL, as B cell activation involves two molecular processes that can create the seminal molecular lesions seen in ARL: 1) immunoglobulin heavy chain gene (IgH) class switch recombination (CSR), a process that involves double-strand DNA breaks and recombination, and 2) somatic hypermutation （SHM），抗体基因可变区域的DNA超名。 IGH CSR和SHM中的错误可能直接导致导致ARL的癌基因突变和/或易位。 IGH CSR和SHM均由APOBEC家族成员激活诱导的胞苷脱氨酶（AICDA）介导。在先前的工作中，我们看到PBMC B细胞AICDA表达在ARL诊断之前升高了几年，而B细胞刺激细胞因子的血清水平也是如此。我们还发现，携带CD40配体（CD40L）的HIV病毒体是T细胞产生的B细胞刺激分子，可以驱动B细胞激活和AICDA表达。鉴于HIV可以通过纳入病毒体中的宿主细胞细胞的刺激分子来有效诱导B细胞的激活，并且B细胞的激活可以有助于ARL的发展，因此，重要的是更好地定义这种与病毒体相关的刺激分子在驱动B细胞激活中的作用，从而促进该研究的特定目的是：1）适用于：1）cd的特定目的：1）cd的特定范围：1）1）cd的特定目的是：1）cd的特定目标。细胞，2）在整个HIV疾病过程中定义CD40L在体内的HIV病毒体上的表达，3）确定ARL的发展是否与CD40L或其他B细胞刺激性分子在血浆中的HIV病毒体的表达升高有关细胞因子和/或，EBV和/或KSHV DNA的血浆水平升高。通过更好地定义CD40L+ HIV和ARL的关联，我们希望阐明这些癌症的发病机理，提供将为未来的风险评估和早期发现以及治疗学发展提供信息的信息。