The complex human T-cell leukemia virus type 1 (HTLV-1) retrovirus encodes several proteins that are unique to the virus within its 3-end region. Among them, the viral transactivator Tax and posttranscriptional regulator Rex are well characterized, and both positively regulate HTLV-1 viral expression. Less is known about the other regulatory proteins encoded in this region of the provirus, including the recently discovered HBZ protein. HBZ has been shown to negatively regulate basal and Tax-dependent HTLV-1 transcription through its ability to interact with specific basic-leucine zipper (bZIP) proteins. In the present study, we found that HBZ reduces HTLV-1 transcription and virion production. We then characterized the interaction between HBZ and the cellular transcription factor CREB. CREB plays a critical role in Tax-mediated HTLV-1 transcription by forming a complex with Tax that binds to viral cyclic AMP-response elements (CREs) located within the viral promoter. We found that HBZ and CREB interact in vivo and directly in vitro, and this interaction occurs through the bZIP domain of each protein. We also found that CREM-Ia and ATF-1, which share significant homology in their bZIP domains with the bZIP domain of CREB, interact with HBZ-bZIP. The interaction between CREB and HBZ prevents CREB binding to the viral CRE elements in vitro and in vivo, suggesting that the reduction in HTLV-1 transcription by HBZ is partly due to the loss of CREB at the promoter. We also found that HBZ displaces CREB from a cellular CRE, suggesting that HBZ may deregulate CREB-dependent cellular gene expression.Human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus that is associated with two distinct diseases: adult T-cell leukemia (ATL), an abnormal proliferation of infected CD4 ϩ T lymphocytes, and HTLV-1-associated myelopathy and/or tropical spastic paraparesis, a neurodegenerative disorder (19,48,49). The molecular mechanisms leading to the development of both diseases are unclear, although the viral protein Tax is postulated to play an important role in these processes. Tax functions as a transcription factor and is essential for strong HTLV-1 transcription. Tax activates transcription through three 21-bp repeats that contain imperfect cyclic AMP responsive elements (called viral CREs) situated within the long terminal repeat of the HTLV-1 genome (1,6,14,15,22,27). Tax does not bind DNA alone but interacts with cellular transcription factors from the ATF/CREB family to form complexes that associate with the DNA. Within these complexes, Tax contacts the GC-rich sequences flanking the CRE core (31,37,38,41). The formation of Tax/CREB/DNA complexes is critical for the recruitment of the cellular coactivators CBP/p300 and subsequent high transcriptional activation of the virus (18,21,32,39,58).A number of cellular factors containing basic leucine zipper (bZIP) motifs have been shown to bind the viral CREs in HTLV-1-infected T cells. These factors included the ATF/ CREB family members (ATF-1, ATF-2, CREB, CREB-2, and CRE...

Background: Antisense transcription in retroviruses has been suggested for both HIV-1 and HTLV-I, although the existence and coding potential of these transcripts remain controversial. Thorough characterization is required to demonstrate the existence of these transcripts and gain insight into their role in retrovirus biology.

Human metapneumovirus (HMPV) is a major pediatric respiratory pathogen with currently no specific treatment or licensed vaccine. Different strategies to prevent this infection have been evaluated, including live-attenuated vaccines (LAV) based on SH and/or G protein deletions. This approach showed promising outcomes but has not been evaluated further using different viral strains. In that regard, we previously showed that different HMPV strains harbor distinct in vitro fusogenic and in vivo pathogenic phenotypes, possibly influencing the selection of vaccine strains. In this study, we investigated the putative contribution of the low conserved SH or G accessory proteins in such strain-dependent phenotypes and generated recombinant wild type (WT) and SH- or G-deleted viruses derived from two different patient-derived HMPV strains, A1/C-85473 and B2/CAN98-75. The ΔSH and ΔG deletions led to different strain-specific phenotypes in both LLC-MK2 cell and reconstituted human airway epithelium models. More interestingly, the ΔG-85473 and especially ΔSH-C-85473 recombinant viruses conferred significant protection against HMPV challenge and induced immunogenicity against a heterologous strain. In conclusion, our results show that the viral genetic backbone should be considered in the design of live-attenuated HMPV vaccines, and that a SH-deleted virus based on the A1/C-85473 HMPV strain could be a promising LAV candidate as it is both attenuated and protective in mice while being efficiently produced in a cell-based system.