Mechanism of activated transcription in the new HTLV-3 virus

描述：直到最近，HTLV家族仅由HTLV-1和HTLV-2病毒组成。我们和其他人最近发现了HTLV-3的存在，它是HTLV组的第三个成员。这种病毒至少在中非存在，但目前尚不清楚其流行情况。在过去发生的多种物种间传播并导致目前HTLV-1和HTLV-2分布的背景下，人们很容易推测这种新发现的人类逆转录病毒可能广泛传播，至少在非洲大陆是如此。我们现在已经对HTLV-3Pyl43前病毒的全长进行了测序。正如预期的那样，HTLV-3Pyl43的序列包含对应于Gag、Poll、env、Tax和rex的ORF。有趣的是，与病毒启动子对应的ITS长末端重复序列只包含两个21bp的重复元件(也称为Tax Responsive Element或TrE)。其他初步数据表明，HTLV-3的Tax3蛋白在体内表达，并引起体液反应。我们还发现Tax3序列包含几个对其功能至关重要的结构域，即PDZ结合域(HTLV-2 Tax中不存在)和CBP/p300结合域。此外，Tax3在细胞内的定位与Taxi非常相似，并且Tax3抑制淋巴细胞中P53的转录活性。最后，我们还证明了Tax3与CBP和p300结合。综上所述，这些结果有力地证明了Tax3与Taxi有一些共同的分子特性。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，以前的分析让我们得出结论，不仅Tax，而且Px区域编码的其他蛋白质(p12、p13、p30以及由负链mRNA编码的HBZ)也参与了病毒的致病。在这一应用中有两个目的，它们包括：Aim I.人类Tax3是一种反式激活和转化蛋白吗？目的II.比较HTLV-3和STLV-3分子克隆，以评估Tax3 PDZ结合域的作用和366bp缺失的影响。因此，我们目前的应用旨在解决一些与新发现的HTLV-3相关的基本和根本问题，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.