Host Defense Regulation by HTLV-1

成人T细胞白血病-淋巴瘤(ATLL)是一种与人类T细胞相关的侵袭性且通常是致命的肿瘤。 细胞白血病病毒1型(HTLV-1)。ATLL是一种CD4辅助T细胞恶性肿瘤，临床表现为 可能进展的慢性疾病，如急性白血病或高度淋巴瘤。所有情侣都吃得很好 常规化疗方案疗效不佳，但用叠氮胸苷(AZT)和 干扰素-a已经在部分患者中产生了长期的临床缓解。鲜为人知的是 ATLL的分子发病机制。目前尚缺乏适合该疾病的动物模型和HTLV-1 转化的肿瘤与原发肿瘤有本质的区别。大多数研究都集中在这一角色上。 病毒癌蛋白Tax，尽管它在原发肿瘤中不表达。HTLV-1与肿瘤发生的研究进展 感染时间和发病时间之间的潜伏期延长使病情更加复杂。 疾病。为了研究这种肿瘤并确定可能对AZT/IFNO(或 其他)治疗方法必须能够接触到大量的初级分离株。与HTLV-1相关的疾病是 在某些美国社区，在非裔加勒比和非裔拉丁社区，存在严重的医疗保健问题。 迈阿密是HTLV-1病毒的流行地区，巴西东北部州的首府萨尔瓦多也是如此， 巴伊亚。通过迈阿密大学和巴伊亚联邦大学之间的合作 已经确定了几个与恶性黑色素瘤的发病机制、治疗和预后有关的重要分子特征。 太棒了。我们定义了两种疾病，一种对AZT/IFNA有反应，另一种对AZT/IFNA有反应 抵抗力强。应答或缺失与核转录因子-kB亚单位组成和干扰素信号转导有关 属性。我们还发现，长期接受抗病毒治疗的缓解期患者 可在外周血单核细胞(PBMC)中检测到的持久性T细胞克隆。我们建议研究 在我们机构和我们的合作者网站上的初学者。我们将跟踪登记在 抗病毒临床试验，以确定敏感和耐药疾病的分子特征。这 与这一总体建议(干扰素和先天性免疫信号)相关的翻译研究有 开始阐明ATLL进展的分子过程以及定义 最有可能从治疗中受益的性行为患者子集。 相关性(请参阅说明)： 与HTLV-1相关的ATLL是一种致命的疾病，主要影响非洲裔加勒比人和非裔美国人 在我们的社区(南佛罗里达)。这种疾病在非洲裔拉芬人中也很常见。的研究。 ATLL存在一些技术困难，而对实际肿瘤的研究需要进入初级 做作的材料。在我们的提案中，我们提出了一项关于AZT/IFNA敏感性和 耐药ATLL与临床试验相结合。我们对这种疾病和我们的项目有丰富的经验 与本申请中的其他两个提案紧密结合。

Adult T cell leukemia-lymphoma (ATLL) is an aggressive and generally fatal tumor associated with Human T cell Leukemia Virus Type 1 (HTLV-1). ATLL, a CD4 helper T cell malignancy, presents clinically as either a chronic disease that may progress, as an acute leukemia or high grade lymphoma. ATLL pafients fare very pooriy with conventional chemotherapeutic regimens, however therapy with azidothymidine (AZT) and interferon alpha (IFN-a) has produced long-term clinical remissions in a subset of patients. Little is known of the molecular pathogenesis of ATLL. Suitable animal models for the disease have been lacking and HTLV-1 transformed lines differ substanfially from the primary tumors. Most research has centered on the role of the viral oncoprotein tax although it is not expressed in primary tumors. Research on HTLV-1 and oncogenesis is further complicated by the prolonged latency between the time of infection and the development of overt disease. In order to study this tumor and identify subgroups of ATLL that may be amenable to AZT/IFNo (or other) therapies one must have access to a large number of primary isolates. HTLV-1 related diseases are a significant health care problem in certain US communities, in afro-Caribbean and afro-Latin communities. Miami is an endemic area for the HTLV-1 virus as is Salvador, the capital of the northeastern Brazilian state, Bahia. Through a collaboration between the University of Miami and the Federal University of Bahia we have identified several important molecular features related to the pathogenesis, therapy and prognosis of ATLL. We have defined two forms of the disease, one that is responsive to AZT/IFNa and another that is resistant. Response or lack thereof correlates with nuclear NF-kB subunit composifion and IFN signaling properties. We have also found that patients in remission while on long-term antiviral therapy have persistent T cell clones detectable in peripheral blood mononuclear cells (PBMC's). We propose to study primary ATLL in pafients at our institution and at our collaborators site. We will follow patients enrolled on an anfiviral clinical trial to determine the molecular characteristics of sensitive and resistant disease. This translational study which is thematically linked to this overall proposal (IFN and innate immune signaling) has great potential to begin to elucidate the molecular processes of ATLL progression as well as define the subset of pafients most likely to benefit from therapy. RELEVANCE (See instructions): HTLV-1 related ATLL is a deadly disease that predominanfiy affects Afro-Caribbean and African Americans in our community (South Florida). The disease is also quite common in Afro-Lafin populafions. The study of ATLL presents some technical difficulties and investigation of the actual tumor requires access to primary pafient material. We present in our proposal a translafional study of the biology of AZT/IFNa sensifive and resistant ATLL coupled with a clinical trial. We have substanfial experience with this disease and our project is closely integrated with the two other proposals in this application.