Genomic and Microenvironment Analysis of HIV-Associated Diffuse Large B-cell Lymphoma (Immuno/Microenvironment)

项目总结/摘要 该提案涉及与“HIV相关合并症、合并感染和 并发症”这项研究将从两个方面解决这一高度优先的要求，包括研究 EBV和HIV的共感染，以及EBV+和EBV-弥漫性大B-之间的分子差异 HIV+患者的淋巴瘤。 HIV相关的弥漫性大B细胞淋巴瘤（HIV+/DLBCL）仍然是一种研究不足的疾病， 这是接受抗逆转录病毒治疗的艾滋病毒感染者死亡的主要原因。虽然有重大的 在分子分类方面，新发DLBCL取得了进展，HIV+/DLBCL落后， 特别是因为它最初被排除在大多数大型研究之外。大约30%的肿瘤 可能是EBV阳性的，可能是淋巴瘤发生的驱动机制， 大多数病例的发病机制尚未得到全面研究。此外，肿瘤 微环境（TME）在淋巴瘤的预后和治疗中起着重要作用，但这一领域 尚未在HIV+/DLBCL中进行研究。我们假设，通过研究基因组景观， TME的HIV+/DLBCL，我们将确定关键的细胞脆弱性和途径，可以提供见解， 为HIV+/EBV阳性与HIV+/EBV阴性DLBCL患者定制新疗法。利用我们 多机构合作，我们计划评估1）HIV+/DLBCL的整个“组学”以及2）研究 利用多光谱免疫荧光结合空间基因表达对HIV+/DLBCL进行TME 数据、EBV状态和基因组数据。3)我们将利用淋巴瘤和白血病分子分析项目 （LLMPP）与他们建立的病理学审查和生物信息学管道，以促进这项研究， 产生重要的数据，我们和世界各地的其他调查人员可以在未来几年使用这些数据， 新的假设，设计针对这种侵袭性疾病的靶向治疗和试验。

PROJECT SUMMARY/ABSTRACT This proposal addresses the high priority statement related to “HIV-associated comorbidities, coinfections, and complications.” This study will be addressing this high priority requirement from two aspects, including the study of co-infection by EBV and HIV, as well as the molecular differences between EBV+ and EBV- diffuse large B- cell lymphoma in HIV+ patients. HIV-associated diffuse large B-cell lymphoma (HIV+/DLBCL) remains an understudied disease and is one of the leading causes of death in persons living with HIV on anti-retroviral therapy. Although there have been significant strides taken with de novo DLBCL in terms of molecular classification, HIV+/DLBCL has lagged behind, particularly because it was originally excluded from most large studies. While approximately 30% of these tumors can be EBV-positive, potentially serving as a driving mechanism for lymphomagenesis, the molecular pathogenesis in the majority of cases have not been comprehensively studied. Additionally, the tumor microenvironment (TME) plays an important role in lymphomas related to prognosis and therapy, but this area has not been investigated in HIV+/DLBCL. We hypothesize that by investigating the genomic landscape and TME of HIV+/DLBCL, we will identify key cellular vulnerabilities and pathways that can provide insights for tailoring novel therapies for patients with HIV+/EBV-positive versus HIV+/EBV-negative DLBCL. Utilizing our multi-institutional collaboration, we plan to evaluate the 1) whole “omics” of HIV+/DLBCL as well as 2) investigate the TME of HIV+/DLBCL using multispectral immunofluorescence in conjunction with spatial gene expression data, EBV-status, and genomic data. 3) We will utilize the Lymphoma and Leukemia Molecular Profiling Project (LLMPP) with their established pathology review and bioinformatics pipeline to facilitate this study which will generate important data that we and other investigators around the world can use in future years to generate new hypothesis, design targeted treatments and trials for this aggressive disease.