Making Sense out of Antisense Transcription in Human T-Cell Lymphotropic Viruses (HTLVs)

Retroviral gene expression generally depends on a full-length transcript that initiates in the 5′ long terminal repeat (LTR), which is either unspliced or alternatively spliced. We and others have demonstrated the existence of an antisense transcript initiating in the 3′ LTR of the Human T-cell Leukemia Virus type 1 (HTLV-1) that is involved in the production of HBZ (HTLV-1 basic leucine zipper (bZIP) factor). HBZ is a Fos-like factor capable of inhibiting Tax-mediated activation of the HTLV-1 LTR by interacting with the cellular transcription factor cAMP-response element-binding protein (CREB) and the pleiotropic cellular coactivators p300/CBP. HBZ can also activate cellular transcription through its interaction with p300/CBP. Interestingly, HBZ has also been found to promote T-lymphocyte proliferation. By down-regulating viral expression and by stimulating T-cell proliferation, HBZ could be essential in the establishment of a chronic infection. Antisense transcription also occurs in the closely related HTLV-2 retrovirus as well as in the recently discovered HTLV-3 and HTLV-4. These antisense transcripts are also involved in the production of retroviral proteins that we have termed Antisense Protein of HTLVs (APH). Like HBZ, the APH proteins are localized in the nucleus of transfected cells and repress Tax-mediated viral transcription

Comparison of Packaging Strategy in Retroviruses and Pararetroviruses

AbstractReverse transcription is not solely a retroviral mechanism. Animal hepadnaviruses, plant caulimoviruses, and badnaviruses have a RNA intermediate which is reverse transcribed into double-stranded DNA genome. Based on this fact, these three groups of viruses have been regrouped under the name of pararetroviruses. Although each one has developed its own strategy to assure an efficient packaging of their genome, it is clear that they have adopted a strategy where encapsidation prepares for initiation of reverse transcription. This is discussed in this review

A modified version of a Fos-associated cluster in HBZ affects Jun transcriptional potency

Like c-Fos, HBZ (HTLV-I bZIP factor) is able to interact with c-Jun but differs considerably from c-Fos in its ability to activate AP-1-responsive genes since HBZ rather inhibits transcriptional activity of c-Jun. To better understand the molecular mechanisms involved in this down-regulation of c-Jun activity, a large number of HBZ/c-Fos chimeras was constructed and analyzed for their ability to interact with c-Jun, to bind to the AP-1 motif and to stimulate expression of a reporter gene containing the collagenase promoter. By this approach, we demonstrate that the DNA-binding domain of HBZ is responsible for its inhibitory effect on the trans-activation potential of c-Jun. However, unexpectedly, we found that exchange of a cluster of six charged amino acids immediately adjacent to the DNA contact region altered significantly transcriptional activity of chimeras. This particular subdomain could be involved in efficient presentation of the AP-1 complex to the transcriptional machinery. To confirm this role, specific residues present in the cluster of HBZ were substituted for corresponding amino acids in c-Fos. Unlike the JunD-activating potential of wild-type HBZ, this mutant was no longer able to stimulate JunD activity, confirming the key role of this particular cluster in regulation of Jun transcriptional potency

JunD/HBZ enhances HBZ enhances HTLV-1 antisense transcription

Infection with the human T-cell leukemia virus type 1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia (ATL), a fatal malignancy characterized by the uncontrolled proliferation of virally infected CD4+ T cells. The HTLV-1 basic leucine zipper factor (HBZ) is believed to contribute to development and maintenance of ATL. Unlike the other HTLV-1 genes, the hbz gene is encoded on the complementary strand of the provirus and therefore is not under direct control of the promoter within the 5′ long terminal repeat (LTR) of the provirus. This promoter can undergo inactivating genetic or epigenetic changes during the course of ATL that eliminates expression of all viral genes except that of hbz. In contrast, repressive modifications are not known to occur on the hbz promoter located in the 3′ LTR, and hbz expression has been consistently detected in all ATL patient samples. Although Sp1 regulates basal transcription from the HBZ promoter, other factors that activate transcription remain undefined. In this study, we used a proviral reporter construct deleted of the 5′ LTR to show that HBZ upregulates its own expression through cooperation with JunD. Activation of antisense transcription was apparent in serum-deprived cells in which the level of JunD was elevated, and elimination of JunD expression by gene knockout or shRNA-mediated knockdown abrogated this effect. Activation through HBZ and JunD additionally required Sp1 binding at the hbz promoter. These data favor a model in which JunD is recruited to the promoter through Sp1, where it heterodimerizes with HBZ thereby enhancing its activity. Separately, hbz gene expression led to an increase in JunD abundance, and this effect correlated with emergence of features of transformed cells in immortalized fibroblasts. Overall, our results suggest that JunD represents a novel therapeutic target for the treatment of ATL

Detection, characterization and regulation of antisense transcripts in HIV-1

© 2007 Landry et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

HTLV-1 HBZ cooperates with JunD to enhance transcription of the human telomerase reverse transcriptase gene (hTERT)

<p>Abstract</p> <p>Background</p> <p>Activation of telomerase is a critical and late event in tumor progression. Thus, in patients with adult-T cell leukaemia (ATL), an HTLV-1 (Human T cell Leukaemia virus type 1)-associated disease, leukemic cells display a high telomerase activity, mainly through transcriptional up-regulation of the human telomerase catalytic subunit (hTERT). The HBZ (HTLV-1 bZIP) protein coded by the minus strand of HTLV-1 genome and expressed in ATL cells has been shown to increase the transcriptional activity of JunD, an AP-1 protein. The presence of several AP-1 binding sites in the hTERT promoter led us to investigate whether HBZ regulates hTERT gene transcription.</p> <p>Results</p> <p>Here, we demonstrate using co-transfection assays that HBZ in association with JunD activates the hTERT promoter. Interestingly, the -378/+1 proximal region, which does not contain any AP-1 site was found to be responsible for this activation. Furthermore, an increase of hTERT transcripts was observed in cells co-expressing HBZ and JunD. Chromatin immunoprecipitation (ChIP) assays revealed that HBZ, and JunD coexist in the same DNA-protein complex at the proximal region of hTERT promoter. Finally, we provide evidence that HBZ/JunD heterodimers interact with Sp1 transcription factors and that activation of hTERT transcription by these heterodimers is mediated through GC-rich binding sites for Sp1 present in the proximal sequences of the hTERT promoter.</p> <p>Conclusion</p> <p>These observations establish for the first time that HBZ by intervening in the re-activation of telomerase, may contribute to the development and maintenance of the leukemic process.</p

The antisense protein of HTLV-2 positively modulates HIV-1 replication

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