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

• 批准号: 9385176
• 负责人: OTONIEL MARTINEZ-MAZA
• 金额: $ 8.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385176
• 关键词: AIDS diagnosis; AIDS related cancer; AIDS-Related Lymphoma; AIDS-Related Non-Hodgkin' 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; CCL17 gene; CCL22 gene; CD4 Positive T Lymphocytes; CD40 Ligand; Cause of Death; Cells; Characteristics; Chronic; DNA; DNA Double Strand Break; Developed Countries; Developing 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; Risk; Risk Assessment; Role; Seminal; Serum; Source; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; TP53 gene; Virion; Work; activation-induced cytidine deaminase; c-myc Genes; cell type; chemokine; cytokine; early detection biomarkers; immune function; in vivo; macrophage; member; monocyte; overexpression; paralogous gene; prophylactic; public health relevance; therapeutic development; virtual

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（由申请方提供）：未经治疗的HIV感染不仅导致T细胞免疫功能的进行性丧失，而且导致慢性多克隆B细胞活化。HIV阳性者患B细胞非霍奇金淋巴瘤的风险也大大增加。几乎所有的艾滋病相关淋巴瘤（ARL）都是B细胞起源的。HIV感染相关的B细胞过度活化被认为在ARL的发生中起核心作用，因为B细胞活化涉及两个分子过程，可以产生在ARL中观察到的精液分子病变：1）免疫球蛋白重链基因（IgH）类别转换重组（CSR），一种涉及双链DNA断裂和重组的过程，和2）体细胞超突变（SHM），抗体基因可变区的DNA超突变。IgH CSR和SHM中的错误可直接导致致癌基因突变和/或易位，从而导致ARL。IgH CSR和SHM均由活化诱导的胞苷脱氨酶（AICDA）介导，AICDA是APOBEC家族的成员。在我们之前的工作中，我们发现在ARL诊断之前，PBMC B细胞AICDA表达升高数年，血清中B细胞刺激性细胞因子水平也升高。我们还发现，携带CD 40配体（CD 40 L）的HIV病毒粒子，T细胞产生的B细胞刺激分子，可以驱动B细胞活化和AICDA表达。考虑到HIV可以通过宿主细胞编码的刺激分子整合到病毒体中来有效地诱导B细胞活化，并且B细胞活化可以有助于ARL的发展，因此更好地定义这种病毒体相关的刺激分子在驱动B细胞活化中的作用是重要的。考虑到这一点，本研究的具体目的是：1）确定CD 40 L + HIV促进B细胞中致癌事件的能力，2）确定在HIV疾病的整个过程中，体内HIV病毒体上CD 40 L的表达，和3）确定ARL的发展是否与来自血浆的HIV病毒体上CD 40 L或其它B细胞刺激分子的表达升高有关，以及具有TFH/TH 17细胞特征的循环T细胞中的基因表达模式、升高的B细胞刺激性细胞因子血清水平和/或升高的EBV和/或KSHV DNA血浆水平。通过更好地定义CD 40 L + HIV和ARL的相关性，我们希望阐明这些癌症的发病机制，提供信息，为未来的风险评估和早期检测以及治疗方法的开发提供信息。