Studies of p30 II and p13 II in HTLV-1 Infection

描述（由申请人提供）：本修订版艾滋病毒/艾滋病及相关 疾病研究合作（FIRCA）申请提出的研究，将 加强两个高生产力的研究小组之间的合作， 美国俄亥俄州州立大学（Lairmore和绿色博士）和 帕多瓦，意大利（Ciminale和D 'Agostino博士）。关键在于继续 这些富有成效的交流是使合作成熟的资金， 提高帕多瓦大学实验室的研究能力。 人类嗜T淋巴细胞病毒1型（HTLV-1）感染导致成人T细胞 白血病/淋巴瘤，作为与HIV-1的共感染发生，并且与 各种免疫介导的疾病。这种复杂的逆转录病毒编码典型的 gag、pol和env基因产物，以及独特的调节和辅助基因产物， 在pX ORF I-IV中编码的基因。病毒辅助蛋白在病毒感染中的关键作用 最近出现了病毒复制。Ciminale博士证明了pl 3” 定位于线粒体，这一特性表明这种蛋白质的独特作用 在HTLV-1的自然历史中。使用HTLV-1的分子克隆， 选择性突变pX ORF I和11，Lairmore博士的实验室是 首先确定p12“、p13”/p301“的功能作用， 在兔模型中的感染和静息T细胞的感染。在 与此同时，我们现在提供的证据表明，p30”作为转录因子的功能， 并通过以下途径差异调节CRE和TRE介导的转录： CBP/p300。总之，我们的实验室处于一个独特的位置， 这些“辅助蛋白”影响复制的机制， HTLV-1的基因表达。具体目标包括： 1.表征p30-与共激活剂p300/CBP的相互作用，以及 测试乙酰化在p30-介导的转录活性中的作用，2. p30”靶向特性的剖析及时间序列的分析 病毒复制过程中p30和p13 mRNA的表达，3.确定 调节亚细胞定位和影响的结构特性 HTLV-1 p13”对线粒体功能的影响。综合设施和专业知识 由拟议的艾滋病相关FIRCA汇集在一起是独特的，富有成效的， 履行福格蒂国际中心的使命， 美国与外国的合作研究。

DESCRIPTION (provided by applicant): This revised HIV-AIDS and Related Illnesses Research Collaboration (FIRCA) application proposes studies that will strengthen a collaboration between two highly productive research groups at The Ohio State University, USA (Drs. Lairmore and Green) and the University of Padova, Italy (Drs. Ciminale and D'Agostino). Critical to the continuation of these productive exchanges are funds to allow the collaborations to mature and to increase the research capacity of laboratories at the University of Padova. Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma, occurs as a co-infection with HIV-1, and is associated with a variety of immune-mediated disorders. This complex retrovirus encodes typical gag, pol, and env gene products, as well as unique regulatory and accessory genes encoded in pX ORF I-IV. Critical roles of the viral accessory proteins in viral replication have recently emerged. Dr. Ciminale demonstrated that pl3" localizes to mitochondria, a property suggesting a unique role for this protein in the natural history of HTLV-1. Using molecular clones of HTLV-1 with selective mutations of pX ORFs I and 11, Dr. Lairmore's laboratory was the first to identify functional roles of p12', p13"/p301' for establishment of infection in the rabbit model and for infection of resting T-cells. In parallel, we now provide evidence that p30" functions as a transcription factor and differentially modulates CRE- and TRE-mediated transcription through CBP/p300. Together, our laboratories are in a unique position to test mechanisms by which these "accessory proteins" influence the replication and gene expression of HTLV-1. Specijc aims that will be addressed include: 1.Characterize the interaction of p30" with the coactivators, p300/CBP, and test the role of acetylation in p30"-mediated transcri tional activity, 2. Dissection of the targeting properties of p30" and analysis of the temporal expression of p30 and p13" mRNAs during virus replication, 3. Determine structural properties that regulate the subcellular localization and influence of HTLV-1 p13" on mitochondrial function. The combined facilities and expertise brought together by the proposed AIDS-related FIRCA are unique, productive, and fulfill the mission of the Fogarty International Center to support collaborative research between the US and foreign countries.