New Models and Treatments for AIDS-related Lymphoma

描述（申请人提供）：eb病毒（EBV）与艾滋病患者b细胞恶性肿瘤相关，迫切需要新的治疗方法来治疗eb病毒诱导的艾滋病患者淋巴瘤。此外，必须开发具有完整人类免疫系统的更好的动物模型，以确定特定病毒蛋白在ebv诱导的淋巴瘤中的作用，并测试新的抗肿瘤疗法。在本提案的目的1中，我们将使用新开发的人源化小鼠模型来阐明两种EBV潜伏蛋白（LMP1和LMP2A）在完整病毒基因组背景下以及在存在或缺乏功能性免疫系统的情况下建立淋巴瘤的作用。由于我们意想不到且有趣的新初步结果表明，当T细胞功能被抑制时，LMP1和LMP2A EBV突变体都可以在人源化小鼠中诱导B细胞淋巴瘤，我们假设LMP1和LMP2A的转化功能在该模型中部分冗余，并且T细胞反应的质量影响LMP1和LMP2A的作用。在Aim 2中，我们将在人源化小鼠模型中检查LMP1/LMP2A双突变体的转化表型，并使用该模型（以及体外研究）来探索LMP1与LMP2A对病毒再激活的影响。我们假设LMP1/LMP2A双突变病毒在人源化小鼠中完全无法形成淋巴瘤，并且LMP1和LMP2A在裂解病毒再激活方面具有相反的作用。最后，在Aim 3中，我们将探索fda批准的关节炎药物来氟米特作为EBV+艾滋病相关淋巴瘤治疗的潜在用途。我们令人兴奋的初步结果表明，来氟米特不仅通过atm依赖机制诱导EBV的裂解性再激活，而且在体外以临床无毒剂量杀死许多不同类型的EBV转化的B细胞（包括EBV+ Burkitt淋巴瘤和淋巴母细胞样细胞系）。我们假设人源化小鼠模型将揭示LMP1/LMP2A在EBV诱导的淋巴瘤中的作用在功能性T细胞存在和不存在的情况下是不同的，并且来氟米特可以用于治疗EBV阳性艾滋病相关淋巴瘤，通过其诱导ATM/p53依赖的裂解性EBV再激活的能力，以及抑制EBV激活的基本细胞通路（包括c-myc， NF-Kappa B和STAT3），这些通路是EBV转化的B细胞生存所必需的。

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is associated with B-cell malignancies in AIDS patients, and new treatments are urgently needed to treat AIDS patients with EBV-induced lymphomas. In addition, better animal models, with intact human immune systems, must be developed to define the roles of specific viral proteins in EBV-induced lymphomas, and to test new anti-tumor therapies. In Aim 1 of this proposal, we will use a newly developed humanized mouse model to clarify the role(s) of two EBV latent proteins (LMP1 and LMP2A) for the establishment of lymphomas in the context of an intact viral genome, and in the presence or absence of a functional immune system. Since our unexpected and intriguing new preliminary results indicate that both the LMP1 and LMP2A EBV mutants can induce B cell lymphomas in humanized mice when T cell function is inhibited, we hypothesize that the transforming functions of LMP1 and LMP2A are partially redundant in this model, and that the quality of the T cell response affects the roles of LMP1 and LMP2A. In Aim 2, we will examine the transforming phenotype of a double LMP1/LMP2A mutant in the humanized mouse model, and use this model (as well as in vitro studies) to explore the effects of LMP1 versus LMP2A on viral reactivation. We hypothesize that the double LMP1/LMP2A mutant virus will be completely defective for lymphoma formation in humanized mice, and that LMP1 and LMP2A have opposing effects on lytic viral reactivation. Finally, in Aim 3, we will explore the potential use f the FDA-approved arthritis drug, leflunomide, as a treatment for EBV+ AIDS-related lymphomas. Our exciting preliminary results show that leflunomide not only induces lytic EBV reactivation through an ATM-dependent mechanism, but that it also kills many different types of EBV-transformed B cells in vitro (including EBV+ Burkitt lymphomas and lymphoblastoid cell lines) at clinically non-toxic doses. We hypothesize that the humanized mouse model will reveal that the roles of LMP1/LMP2A in EBV-induced lymphomas are different in the presence versus absence of functional T cells, and that leflunomide can be used to treat EBV-positive AIDS-related lymphomas both through its ability to induce ATM/p53-dependent lytic EBV reactivation, and to inhibit essential EBV-activated cellular pathways (including c-myc, NF-Kappa B, and STAT3) that are required for the viability of EBV-transformed B cells.