HBZ Protein Research Articles

Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles

AbstractDisease development in human T-cell leukemia virus type 1 (HTLV-1)–infected individuals is positively correlated with the level of integrated viral DNA in T cells. HTLV-1 replication is positively regulated by Tax and Rex and negatively regulated by the p30 and HBZ proteins. In the present study, we demonstrate that HTLV-1 encodes another negative regulator of virus expression, the p13 protein. Expressed separately, p13 localizes to the mitochondria, whereas in the presence of Tax, part of it is ubiquitinated, stabilized, and rerouted to the nuclear speckles. The p13 protein directly binds Tax, decreases Tax binding to the CBP/p300 transcriptional coactivator, and, by reducing Tax transcriptional activity, suppresses viral expression. Because Tax stabilizes its own repressor, these findings suggest that HTLV-1 has evolved a complex mechanism to control its own replication. Further, these results highlight the importance of studying the function of the HTLV-1 viral proteins, not only in isolation, but also in the context of full viral replication.

The HTLV-1 hbz antisense gene indirectly promotes tax expression via down-regulation of p30-II mRNA

Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is transcribed from the antisense genomic DNA strand and functions differently in its RNA and protein forms. To distinguish between the roles of hbz mRNA and HBZ protein, we generated mutants in a proviral clone that specifically disrupt the hbz gene product. A proviral clone with a splice acceptor mutation that disrupts expression of the predominant hbz mRNA resulted in lower levels of tax mRNA. Heterologous hbz expression restored Tax activity in cells expressing this mutant clone. In contrast, proviral mutants that disrupt only HBZ protein did not affect levels of tax mRNA. Expression of hbz resulted in lower levels of p30II mRNA. Mutation of p30II overcame the effects of the splice acceptor mutation of hbz, and restored tax expression. Thus, there is a complex interplay of viral regulatory proteins controlling levels of HTLV-1 gene expression. The pathogenic role of HBZ alone or combined with Tax is currently under study in transgenic mice, and will be discussed.

Tax-mediated re-routing of the HTLV-1 p13 protein to nuclear speckles

Human T-cell Leukemia Virus type-1 (HTLV-1) is highly immunogenic and has low variability so tight regulation of its expression is essential for virus maintenance in vivo. HTLV-1 replication is positively regulated by Tax and Rex, and negatively by the p30 and HBZ proteins. Here, we demonstrate that HTLV-1 encodes another negative regulator of virus expression, the p13 protein. Expressed separately, p13 localizes to the mitochondria, but in the presence of Tax, p13 is stabilized, and re-routed to the nuclear speckles. The p13 protein directly binds Tax, decreases Tax binding to the CBP/ p300 transcriptional co-activator and, by reducing Tax transcriptional activity, suppresses viral expression. These findings suggest that HTLV-1 has evolved a complex mechanism to control its own replication through regulation of positive and negative viral proteins. Further, these results emphasize the importance of studying the function of the HTLV-1 viral proteins, not only in isolation, but also in the context of full viral replication.

Opposite effect of Valproate on Tax and HBZ expression in T-lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients

A determinant of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) development is HTLV-1-infected cell burden. Viral proteins Tax and HBZ, encoded by the positive and negative strands of the pX region respectively, play a key role in HTLV-1 persistence. Tax drives CD4+ T-cell clonal expansion but is the immunodominant antigen. Valproate (VPA), an histone deacetylase inhibitor, has been proposed to trigger Tax expression and expose latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA treatment on Tax, Gag and HBZ expression in cultured lymphocytes from asymptomatic HTLV-1 carriers and HAM/TSP patients. Around one-fifth of provirus-positive CD4+ T cells spontaneously became Tax-positive. The estimation rose up to two-thirds of Tax-positive infected cells when VPA was added. VPA enhanced Gag p19 protein release. Tax and Gag mRNA levels spontaneously peaked, before a decline concomitant to HBZ mRNA increase. VPA treatment enhanced and prolonged Tax mRNA expression, while it blocked HBZ expression. This is the first ex vivo study on the balance between Tax and HBZ expression (i.e. sense and antisense transcription). Our data suggest that besides modulation of the expression of Tax, another mechanism involving repression of HBZ may determine the outcome of VPA treatment on HTLV-1-infected cell proliferation and survival.

Successful development of novel monoclonal antibodies against HTLV-1 bZIP factor and their applications in studying the pathogenesis of HAM/TSP

Methods We have generated rat and human monoclonal antibodies against HBZ by hybridoma methodology and a phage display system, and developed the ELISA system for the detection of HBZ protein and anti-HBZ antibodies. Using these reagents, we analyzed the expression of HBZ protein in plasma and peripheral blood mononuclear cells (PBMCs) of HTLV-1 infected individuals as well as HTLV-1 infected cell lines. Then the results were compared with the real time PCR data.

Expression of hbz mRNA promotes survival in HTLV-1-infected cells with high DNA damage

Background HTLV1 may exert an initial pro-apoptotic stimulus via Tax-induced DNA damage. On the other hand, Hbz protein antagonizes some Tax effects on gene expression and hbz mRNA has been proposed as essential for maintaining oncogenesis. We hypothesize that expression of the hbz gene contributes to overcoming the pro-apoptotic signals in HTLV1 infected T-cells with DNA damage. To test this hypothesis we studied the expansion of infected cells with high DNA damage and investigated whether hbz mRNA supports survival of those cells.

HTLV-1 persistence in vivo: clonality, dynamics and immune response

HTLV-1 propagates in the host by two parallel mechanisms: infectious spread, i.e. direct transfer of virions from cell to cell via the virological synapse; and mitotic spread, i.e. proliferation of HTLV-1-infected T cell clones. During chronic infection, mitotic spread predominates, generating very large clones in some individuals. Yet the reasons for the remarkable variation within and between hosts in the abundance of HTLV-1-infected clones remain unknown. We aim to identify and quantify the selection forces that determine the size of HTLV-1-infected T cell clones in vivo and hence the risk of the associated inflammatory and malignant diseases. We shall summarize evidence from host and viral genetics, cellular immunology and high-throughput proviral integration site analysis that: 1. The ‘quality’ or efficiency of a person’s genetically-determined cytotoxic T lymphocyte (CTL) response to the HBZ protein is a major determinant of that person’s proviral load and the risk of inflammatory diseases. 2. The chief determinant of CTL quality is the host genotype in HLA Class 1 and Killer cell Immunoglobulin-like Receptor (KIR) loci. 3. The CTL response to the Tax protein is immunodominant but does not protect against HAM/TSP. 4. The site and orientation of the HTLV-1 provirus integrated in the T cell genome determine the size of each T cell clone in the host. 5. Negative selection on the virus dominates during chronic infection: we postulate that this selection is exerted by CTLs.

HTLV-3 and HTLV-4 antisense proteins activate JunB-, c-Jun- and JunD-dependent transcription

Background The antisense transcript-encoded HBZ protein acts upon viral and cellular gene expression through its modulation of the activation of transcription factors such as Jun family members. A possible link between HBZ and ATL development has also been highlighted. HTLV-3 and HTLV-4 are two newly discovered human retroviruses closely related to HTLV-1; no known diseases have yet been associated to these viruses. Based on previous in silico analyses, our aim was to test for the presence of antisense transcripts in these new viruses and to functionally assess these viral proteins. Results By RT-PCR analyses, HTLV-3 and HTLV-4 were shown to produce spliced antisense transcripts termed APH (Antisense Protein of HTLV)-3 and APH-4. Confocal microscopy analyses of cells expressing Myc- or GFP-tagged APH-3 and APH-4 showed distinct localization but partial colocalization with HBZ to the nucleus and the nucleoli. Using LTR-luciferase constructs, we demonstrated that APH-3 and APH-4 inhibited Tax1 and Tax3 transactivation of respective LTRs. In transfection experiments with a collagenase promoter-driven luciferase reporter construct, we showed that APH-3 and APH-4 modulated JunB- and c-Jun-dependent transcription differently from HBZ. Deletion mutants indicated that this upregulation of the transactivation potential of Jun factors was mediated through the atypical bZIP domain of APH-3 and APH-4. Conclusion We show that HTLV-3 and HTLV-4 express new viral proteins, APH-3 and APH-4, which modulate Jundependent transcription differently from HBZ. These data underscore the importance of our study on APH-3 and APH-4 to help in better understanding the role of HBZ in the development of ATL.

Susceptibility of HBZ and Tax expressing primary HTLV-1+ T cell clones to CTL lysis

Host cytotoxic lymphocyte (CTL) responses play an essential role in limiting clonal expansion of infected CD4+ T cells in HTLV-1+ individuals. We have reported that individuals who possess HLA class 1 alleles that strongly bind peptides from HTLV-1 basic leucine zipper protein (HBZ) have a lower proviral load and are less likely to develop HAM/TSP. In general, peptides from HBZ bind weakly to MHCI, and we detected low frequencies of HBZ-specific CD8+ T cells in ≈25% of infected individuals. Despite its poor immunogenicity, high avidity CTL lines can be generated in vitro which efficiently lyse HBZ-presenting cells [1]. HBZ mRNA, encoded on the antisense strand of the viral genome, can induce proliferation of T cells, and once translated it can inhibit expression of Tax. HBZ mRNA is expressed in vivo in the majority of infected individuals, however, HBZ protein expression levels are extremely low in PBMCs ex vivo. To investigate the relationship between Tax and HBZ expression in naturally infected CD4+ T cells at the single cell level, we cloned T cells from individuals with HAM/TSP. We detected HBZ mRNA in all clones tested. In contrast, a subset of infected clones stably expressed Tax protein. Thus, individual clones may have a unique viral gene expression profile, with differing susceptibility to lysis by HTLV-1 specific CTL. We are testing the hypothesis that targeting of Tax– clones by HBZ-specific CTL eliminates clones which otherwise escape lysis by abundant Tax-specific CTL.

HTLV-1 HBZ protein inhibits IRF3-mediated innate immune responses

The bZIP factor (HBZ) is an HTLV-1 regulatory protein encoded by anti-sense transcription of the HTLV-1 genome. HBZ mRNA expression correlates with clinical disability in HAM/TSP patients – and can be reversed by interferon (IFN) therapy. Sporadic evidence suggests that HBZ may have a negative role on interferon signalling. Activation of IRF3-dependent IFN signalling – either direct induction of IFNβ, viral restriction factors or interferon stimulated genes (ISGs) – is crucial for TLR and RLR mediated antiviral response. Thus, we sought to determine whether HBZ can impair IRF3-mediated innate immune responses. Over-expression of active forms of RIG-I, MAVS, TBK1, IKKe or IRF3 alone drive an antiviral response – however, in the presence of an HBZ expression vector, IFNβ responses were abrogated by 50-70%. In contrast, HBZ enhanced IRF7-dependent responses. In confirmation, both PBMC and human astrocytes transfected with HBZ and subsequently stimulated with IFN-triggering ligands (LPS, PolyI:C, VSV, Sendai virus and HTLV-1 virions), exhibited impaired IRF3-dependent signalling as compared with controls. As IRF3 is known to bind other bZIP proteins, further studies are underway to delineate the nature of IRF-HBZ interactions. Identifying such a mechanism may explain an enhanced risk of neurologic infection, as we show that chronically HTLV-1 infected astrocytes gradually increase and maintain long-term HBZ expression. Defining the immunomodulatory properties of HTLV-1 HBZ protein will provide a vital contribution toward understanding clinical outcome and risk of opportunistic infection associated with HTLV-1 infection.

Potential interference of HTLV-1 HBZ protein with the DNA damage response pathway

It takes decades after infection by HTLV-1 for an individual to develop adult T-cell leukemia/lymphoma. This disease is associated with increase genomic instability, due to an alteration of the DNA damage response of the infected cells. While this alteration has been attributed to the viral protein Tax, we found that the viral protein HBZ might also play a role in this process. In this study, we found that expression of HBZ in Jurkat cells increases the sensitivity of these cells to Etoposide treatment. Etoposide phosphate is an anticancer drug that induces DNA damage. This drug acts by forming a ternary complex with DNA and Topoisomerase II, leading to inhibition of the enzyme and creating double strand breaks. As a result, errors are incorporated into the DNA and the cells undergo apoptosis. We treated a stable cell line expressing HBZ, or the backbone vector, with 12.5μM Etoposide for 24 hrs. To determine the percentage of viable cells as well as cells in early or late apoptosis, we used a combination of Propidium iodide and Annexin V staining. Interestingly, we found that the cells expressing HBZ exhibit a 16% increase in total apoptotic cells and a13 % increase in late apoptotic cells compared to the cells expressing the backbone vector. This result suggests that HBZ increases DNA damage following Etoposide treatment. Current and future work investigates the effect of HBZ on other activators of the DNA damage response and tries to delineate the effect of HBZ on the regulation of the DNA damage response pathway.

NF-κB hyper-activation by HTLV-1 Tax induces cellular senescence, but can be alleviated by the viral anti-sense protein HBZ

Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotrpic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induction by Tax is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that downregulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyperactivation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis.

NF-κB Hyper-Activation by HTLV-1 Tax Induces Cellular Senescence, but Can Be Alleviated by the Viral Anti-Sense Protein HBZ

Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21CIP1/WAF1 and p27KIP1, which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21CIP1/WAF1-/p27KIP1-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induced by Tax in HeLa cells is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27KIP1 protein and p21CIP1/WAF1 mRNA respectively. Finally, we show that down-regulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyper-activation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis.

HTLV-1 HBZ Protein Deregulates Interactions between Cellular Factors and the KIX Domain of p300/CBP

The complex retrovirus human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. Deregulation of cellular transcription is thought to be an important step for T-cell transformation caused by viral infection. HTLV-1 basic leucine zipper factor (HBZ) is one of the viral proteins believed to be involved in this process, as it deregulates the expression of numerous cellular genes. In the context of the provirus, HBZ represses HTLV-1 transcription, in part, by binding to the homologous cellular coactivators p300 and CBP. These coactivators play a central role in transcriptional regulation. In this study, we determined that HBZ binds with high affinity to the KIX domain of p300/CBP. This domain contains two binding surfaces that are differentially targeted by multiple cellular factors. We show that two φXXφφ motifs in the activation domain of HBZ mediate binding to a single surface of the KIX domain, the mixed-lineage leukemia (MLL) binding surface. Formation of this interaction inhibits binding of MLL to the KIX domain while enhancing the binding of the transcription factor c-Myb to the opposite surface of KIX. Consequently, HBZ inhibits transcriptional activation mediated by MLL and enhances activation mediated by c-Myb. CREB, which binds the same surface of KIX as c-Myb, also exhibited an increase in activity through HBZ. These results indicate that HBZ is able to alter gene expression by competing with transcription factors for the occupancy of one surface of KIX while enhancing the binding of factors to the other surface.

The HTLV-1 hbz antisense gene indirectly promotes tax expression via down-regulation of p30II mRNA

Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) is transcribed from the antisense genomic DNA strand and functions differently in its RNA and protein forms. To distinguish between the roles of hbz mRNA and HBZ protein, we generated mutants in a proviral clone that specifically disrupt the hbz gene product. A proviral clone with a splice acceptor mutation that disrupts expression of the predominant hbz mRNA resulted in lower levels of tax mRNA. Heterologous hbz expression restored Tax activity in cells expressing this mutant clone. In contrast, proviral mutants that disrupt HBZ protein did not affect levels of tax mRNA. Expression of hbz resulted in lower levels of p30 II mRNA. Mutation of p30 II overcame the effects of the splice acceptor mutation of hbz, and restored tax expression. Thus, there is a complex interplay of viral regulatory proteins controlling levels of HTLV-1 gene expression.

Infantile Hemangioma: A Tumor Involving Hemogenic Endothelium with Erythropoetic Potential

AbstractAbstract 4305 BackgroundInfantile hemangioma (IH) is a tumor of the microvasculature predominantly composed of proliferating endothelial cells, but also contains progenitor cells of mesenchymal and hematopoietic lineages. We have previously shown that IH has a primitive mesodermal origin. Here we investigated expression of hematopoietic associated proteins (Tal-1, GATA-2, CD133 & CD34) as well as the erythropoietin receptor (EPOR) and the embryonically-associated hemoglobin zeta chain (HBZ) by both the cells of the endothelium and the cells emanating from proliferating IH explants. Additionally we investigated if the cells emanating from the explants generate erythrocytes in vitro. PurposeTo investigate the expression of hematopoietic associated proteins and the primitive erythropoietic capacity of proliferating IH. MethodsProliferating IH biopsies from 5 patients were (i) processed for IHC staining for Tal-1, GATA-2, CD133, CD34, HBZ and EPOR; (ii) used to determine the relative expression of Tal-1, GATA-2, CD133, CD34, HBZ & EPOR transcripts by qRT-PCR; (ii) cultured as explants using our in vitro model and differentiated the cells down the erythropoietic lineage. ResultsIHC showed that the cells that line the endothelium forming the capillaries of proliferating IH expressed Tal-1, GATA-2, CD133, CD34, HBZ and EPOR. qRT-PCR confirmed the IHC data as abundant expression mRNA transcripts for the same proteins was detected in both the tissue and the cells emanating from the cultured explants. Following 5 months in culture morphological biconcave cells were visible, and were confirmed to be erythrocytes by immunoreactivity to the erythrocyte-specific cell surface marker glycophorin A. ConclusionThe mRNA and protein expression of hematopoietic associated proteins in proliferating IH supports our previous studies showing this tumor expressing markers of primitive mesoderm and confirms a hemogenic endothelium phenotype. The expression of the primitive erythropoiesis-associated proteins HBZ and EPOR by proliferating IH and its functional ability of proliferating IH explants to form erythrocytes in vitro confirms the erythropoietic potential. Proliferating IH thus represents an extra-medullary site of tumor-associated erythropoiesis. Disclosures:No relevant conflicts of interest to declare.

Requirement of the human T-cell leukemia virus p12 and p30 products for infectivity of human dendritic cells and macaques but not rabbits

AbstractThe identification of the genes necessary for human T-cell leukemia virus (HTLV-1) persistence in humans may provide targets for therapeutic approaches. We demonstrate that ablation of the HTLV-1 genes encoding p12, p30, or the HBZ protein, does not affect viral infectivity in rabbits and in this species, only the absence of HBZ is associated with a consistent reduction in virus levels. We observed reversion of the HTLV-1 mutants to the HTLV-1 wild-type genotype in none of the inoculated rabbits. In contrast, in macaques, the absence of HBZ was associated with reversion of the mutant virus to the wild-type genotype in 3 of the 4 animals within weeks from infection. Similarly, reversion to the wild type was observed in 2 of the 4 macaque inoculated with the p30 mutant. The 4 macaques exposed to the p12 knock remained seronegative, and only 2 animals were positive at a single time point for viral DNA in tissues. Interestingly, we found that the p12 and the p30 mutants were also severely impaired in their ability to replicate in human dendritic cells. These data suggest that infection of dendritic cells may be required for the establishment and maintenance of HTLV-1 infection in primate species.

HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection

CD8+ T cells can exert both protective and harmful effects on the virus-infected host. However, there is no systematic method to identify the attributes of a protective CD8+ T cell response. Here, we combine theory and experiment to identify and quantify the contribution of all HLA class I alleles to host protection against infection with a given pathogen. In 432 HTLV-1-infected individuals we show that individuals with HLA class I alleles that strongly bind the HTLV-1 protein HBZ had a lower proviral load and were more likely to be asymptomatic. We also show that in general, across all HTLV-1 proteins, CD8+ T cell effectiveness is strongly determined by protein specificity and produce a ranked list of the proteins targeted by the most effective CD8+ T cell response through to the least effective CD8+ T cell response. We conclude that CD8+ T cells play an important role in the control of HTLV-1 and that CD8+ cells specific to HBZ, not the immunodominant protein Tax, are the most effective. We suggest that HBZ plays a central role in HTLV-1 persistence. This approach is applicable to all pathogens, even where data are sparse, to identify simultaneously the HLA Class I alleles and the epitopes responsible for a protective CD8+ T cell response.

Identification of bZIP Interaction Partners of Viral Proteins HBZ, MEQ, BZLF1, and K-bZIP Using Coiled-Coil Arrays

Basic-region leucine-zipper transcription factors (bZIPs) contain a segment rich in basic amino acids that can bind DNA, followed by a leucine zipper that can interact with other leucine zippers to form coiled-coil homo- or heterodimers. Several viruses encode proteins containing bZIP domains, including four that encode bZIPs lacking significant homology to any human protein. We investigated the interaction specificity of these four viral bZIPs by using coiled-coil arrays to assess self-associations as well as heterointeractions with 33 representative human bZIPs. The arrays recapitulated reported viral-human interactions and also uncovered new associations. MEQ and HBZ interacted with multiple human partners and had unique interaction profiles compared to any human bZIPs, whereas K-bZIP and BZLF1 displayed homospecificity. New interactions detected included HBZ with MAFB, MAFG, ATF2, CEBPG, and CREBZF and MEQ with NFIL3. These were confirmed in solution using circular dichroism. HBZ can heteroassociate with MAFB and MAFG in the presence of MARE-site DNA, and this interaction is dependent on the basic region of HBZ. NFIL3 and MEQ have different yet overlapping DNA-binding specificities and can form a heterocomplex with DNA. Computational design considering both affinity for MEQ and specificity with respect to other undesired bZIP-type interactions was used to generate a MEQ dimerization inhibitor. This peptide, anti-MEQ, bound MEQ both stably and specifically, as assayed using coiled-coil arrays and circular dichroism in solution. Anti-MEQ also inhibited MEQ binding to DNA. These studies can guide further investigation of the function of viral and human bZIP complexes.

Antagonistic effect of the tumor suppressor Menin and the HBZ protein of HTLV-1 on telomerase activity

Background HTLV-1 is a retrovirus responsible for adult T-cell leukemia (ATL) in 5% of infected people. ATL is characterised by a monoclonal proliferation of infected CD4+ T lymphocytes in which a high telomerase activity associated to a poor prognosis has been observed [1]. Furthermore, HBZ is the only viral protein clearly detectable in all ATL patient samples. This protein has been shown to up-regulate the transcription of the catalytic subunit of telomerase, hTERT. Therefore interaction of HBZ with AP-1 transcription factor JunD on the proximal promoter of hTERT is required to up-regulate the gene [2].