MECHANISM OF ACTIVATED TRANSCRIPTION IN THE NEW HTLV-3 VIRUS - 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.
