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

描述（由申请人提供）：未经治疗的HIV感染不仅会导致T细胞免疫功能的进行性丧失，还会导致慢性多克隆B细胞活化。HIV+患者发生B细胞非霍奇金淋巴瘤的风险也大大增加。几乎所有艾滋病相关淋巴瘤（ARL）都是源于B细胞。HIV感染相关的B细胞过度激活被认为在ARL的发生中起着核心作用，因为B细胞激活涉及两个分子过程，可以产生ARL中所见的精囊性分子病变：1)免疫球蛋白重链基因（IgH）类开关重组（CSR），一个涉及双链DNA断裂和重组的过程；2)体细胞超突变（SHM），抗体基因可变区域的DNA超突变。IgH CSR和SHM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都是由活化诱导胞苷脱氨酶（AICDA）介导的，AICDA是APOBEC家族的一员。在我们之前的工作中，我们发现PBMC B细胞AICDA表达在ARL诊断前几年升高，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病毒粒子可以驱动B细胞活化和AICDA表达，CD40L是T细胞产生的B细胞刺激分子。鉴于HIV可以通过宿主细胞编码的刺激分子结合到病毒粒子中有效地诱导B细胞活化，并且B细胞活化可以促进ARL的发展，因此更好地定义这种病毒粒子相关的刺激分子在驱动B细胞活化中的作用是很重要的。1)定义CD40L + HIV的能力促进B细胞的致癌事件,2)定义的表达CD40L在体内HIV病毒粒子,在艾滋病的过程中,和3)确定陆军研究实验室的发展与提升相关的表达CD40L或其他B cell-stimulatory分子从血浆HIV病毒粒子,以及循环T细胞的基因表达模式的特点是TFH / TH17细胞,血清水平升高的B细胞,刺激细胞因子和/或,血浆EBV和/或KSHV DNA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制，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。

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.