Mechanism of activated transcription in the new HTLV-3 virus

描述：直到最近，HTLV家族仅包括HTLV-1和HTLV-2病毒。我们和其他人最近发现了HTLV-3的存在，这是HTLV组织的第三个成员。这种病毒至少在中非存在，但其流行程度目前尚不清楚。在过去发生的多种物种间传播的背景下，导致HTLV-1和HTLV-2在今天的分布，因此很容易推测这种新发现的人类逆转录病毒可能广泛传播，至少在非洲大陆。我们现在已经对全长HTLV-3Pyl43原病毒进行了测序。果然，HTLV-3Pyl43序列包含gag、pol、env、tax和rex对应的orf。有趣的是，它的长末端重复序列对应于病毒启动子，只包含两个21-bp重复元件（也称为税收响应元件或TRE）。其他初步数据表明HTLV-3中的Tax3蛋白在体内表达并引起体液反应。我们还表明，Tax3序列包含几个对其功能至关重要的结构域，即PDZ结合结构域（HTLV-2 Tax中没有）和CBP/p300结合结构域。此外，Tax3的细胞内定位与Taxi非常相似，并且Tax3在淋巴细胞中抑制p53的转录活性。最后，我们还证明了Tax3结合CBP和p300。总之，这些结果有力地证明了Tax3与Taxi具有一些相同的分子特性。长期目标是确定HTLV-3是否像HTLV-1一样是一种致癌病毒。我们的假设是，由于其结构域与Taxi同源，pX编码的蛋白Tax3是一种转化蛋白。我们的理论基础是基于HTLV-1的数据，先前的分析使我们得出结论，不仅是Tax，还有其他由pX区域编码的蛋白质（p12, p13， p30以及由负链mRNA编码的HBZ）参与了病毒的发病机制。本申请有两个目的，它们包括：目的一、人类Tax3是一个转录激活子和转化蛋白吗？和Aim II。比较HTLV-3和STLV-3分子克隆，评估Tax3 PDZ结合域的作用和366 bp缺失的影响。因此，我们目前的申请旨在解决与新发现的HTLV-3相关的一些基本和基本问题，并确定其在发病机制中的作用。

DESCRIPTION: Until recently, the HTLV family comprised only the HTLV-1 and HTLV-2 virus. We and others have recently uncovered the existence of HTLV-3, a third member of the HTLV group. This virus is present at least in Central Africa, but its prevalence is currently unknown. In the context of the multiple interspecies transmissions which occurred in the past and led to the present day distribution of the HTLV-1 and HTLV-2, it is thus very tempting to speculate that this newly discovered human retrovirus might be widespread, at least in the African continent. We have now sequenced the full-length HTLV-3Pyl43 provirus. As expected, the sequence of HTLV-3Pyl43 contains ORFs corresponding to gag, pol, env, tax and rex. Interestingly, its Long Terminal Repeat sequences which correspond to the viral promoter, contain only two 21-bp repeat elements (also named Tax Responsive Element or TRE). Other preliminary data indicates that the Tax3 protein from HTLV-3 is expressed in vivo and elicits a humoral response. We have also shown that Tax3 sequence contains several domains that are critical for its function, i.e. a PDZ binding domain (which is absent from HTLV-2 Tax) and CBP/p300 binding domains. Furthermore, Tax3 intracellular localization is very similar to that of Taxi, and that Tax3 represses p53 transcriptional activity in lymphocytes. Finally, we also demonstrated that Tax3 binds CBP and p300. Altogether, these results strongly demonstrate that Tax3 shares several molecular properties with Taxi. The long term goal is to determine whether HTLV-3 is, as HTLV-1, an oncogenic virus. Our hypothesis is that due to its domains homologies with Taxi, the pX encoded protein Tax3 is a transforming protein. Our rationale is based on data from HTLV-1 where previous analyses have allowed us to conclude that, not only Tax, but also other proteins encoded by the pX region (p12, p13, p30 as well as HBZ that is encoded by a minus strand mRNA) are involved in the viral pathogenesis. There are two aims in this application and they include: Aim I. Is human Tax3 a transactivator & transforming protein? and Aim II. Comparison between HTLV-3 and STLV-3 molecular clones to assess the role of the Tax3 PDZ binding domain and the impact of the 366 bp deletion. Therefore, our current application aims to address some of the basic and fundamental questions that are related to the newly discovered HTLV-3 and define its role in pathogenesis.