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

描述(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细胞的激活。在HIV阳性的人群中，罹患B细胞性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)都起源于B细胞。HIV感染相关的B细胞过度激活被认为在ARL的发生中起核心作用，因为B细胞激活涉及两个分子过程，可造成ARL中的精液分子损害：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)体细胞高突变(SHM)，抗体基因可变区的DNA过度突变。IgH、CSR和SHM的错误可直接导致癌基因突变和/或易位，从而导致ARL。IgH、CSR和SHM均由APOBEC家族成员激活诱导型胞苷脱氨酶(AICDA)介导。在我们之前的工作中，我们看到在ARL诊断之前的几年里，PBMC B细胞AICDA的表达和血清B细胞刺激性细胞因子水平都是升高的。我们还发现，携带CD40配体的HIV病毒粒子(CD40L)可以驱动B细胞的激活和AICDA的表达。CD40L是一种由T细胞产生的B细胞刺激分子。鉴于HIV可以通过整合到病毒粒子中的宿主细胞编码的刺激分子有效地诱导B细胞激活，并且B细胞的激活可以促进ARL的发展，考虑到这一点，更好地确定这种病毒相关刺激分子在驱动B细胞激活中的作用是很重要的，本研究的具体目的是：1)确定CD40L+HIV促进B细胞致癌事件的能力；2)在整个HIV疾病的过程中，定义体内HIV病毒粒子上CD40L的表达；以及3)确定ARL的发展是否与血浆中HIV病毒粒子上CD40L或其他B细胞刺激分子的表达增加有关，以及TFH/TH17细胞特有的循环T细胞基因表达模式，血清B细胞刺激细胞因子水平升高，和/或血浆EBV和/或KSHV DNA水平升高。通过更好地定义CD40L+HIV和ARL之间的联系，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工作以及治疗的发展提供信息。

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.