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1
Lin, Jennifer, and Bryan R. Cullen. "Analysis of the Interaction of Primate Retroviruses with the Human RNA Interference Machinery." Journal of Virology 81, no. 22 (September 12, 2007): 12218–26. http://dx.doi.org/10.1128/jvi.01390-07.
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ABSTRACT The question of whether retroviruses, including human immunodeficiency virus type 1 (HIV-1), interact with the cellular RNA interference machinery has been controversial. Here, we present data showing that neither HIV-1 nor human T-cell leukemia virus type 1 (HTLV-1) expresses significant levels of either small interfering RNAs or microRNAs in persistently infected T cells. We also demonstrate that the retroviral nuclear transcription factors HIV-1 Tat and HTLV-1 Tax, as well as the Tas transactivator encoded by primate foamy virus, fail to inhibit RNA interference in human cells. Moreover, the stable expression of physiological levels of HIV-1 Tat did not globally inhibit microRNA production or expression in infected human cells. Together, these data argue that HIV-1 and HTLV-1 neither induce the production of viral small interfering RNAs or microRNAs nor repress the cellular RNA interference machinery in infected cells.
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Cleveland, Susan M., and Utpal P. Dave. "Insertional Activation of GLI2 in Adult T-Cell Leukemia/Lymphoma." Blood 110, no. 11 (November 16, 2007): 4149. http://dx.doi.org/10.1182/blood.v110.11.4149.4149.
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Abstract Retroviruses induce cancer by integrating into the cellular genome and activating oncogenes or inactivating tumor suppressor genes. Human T-cell Leukemia Virus type 1 (HTLV-1), a complex retrovirus, induces Adult T-cell Leukemia/Lymphoma (ATLL) after a latency of over 30 years and in only 5% of carriers. The long latency and incomplete penetrance is similar to how slow transforming retroviruses induce cancer in mice and imply multiple oncogenic “hits” need to accumulate for clinically apparent disease. Insertional mutagenesis may be one mechanism by which ATLL develops. We used splinkerette-PCR to clone and map insertion sites from an HTLV-1 infected T-cell line, Hut-102. We identified an HTLV-1 insertion 5′ of the GLI2 gene, formerly known as Tax-Helper-Protein-1. We found GLI2 was up-regulated by promoter insertion. Interestingly, we found GLI2 protein occupied the HTLV-1 Long Terminal Repeat. The effect of GLI2 expression on viral expression was investigated by knockdown of GLI2 in Hut-102 cells. Our results show that retroviral insertional mutagenesis can be an important mechanism in HTLV-1-induced leukemias and lymphomas.
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Lemasson, Isabelle, Nicholas J. Polakowski, Paul J. Laybourn, and Jennifer K. Nyborg. "Transcription Regulatory Complexes Bind the Human T-Cell Leukemia Virus 5′ and 3′ Long Terminal Repeats To Control Gene Expression." Molecular and Cellular Biology 24, no. 14 (July 15, 2004): 6117–26. http://dx.doi.org/10.1128/mcb.24.14.6117-6126.2004.
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ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that integrates randomly into the T-cell genome. Two long terminal repeats (LTRs) flank the integrated provirus. The upstream and downstream LTRs carry identical promoter sequences. Studies with other retroviruses suggest that the downstream promoter is silent and that RNA polymerases initiating at the upstream promoter proceed through the 3′ LTR. In this study, we used the chromatin immunoprecipitation assay to compare the binding of transcription regulatory proteins at both the upstream and downstream promoters in HTLV-1-infected cell lines and adult T-cell leukemia-lymphoma cells. Unexpectedly, we detected a nearly equal distribution of activator (Tax, CREB, ATF-1, ATF-2, c-Fos, and c-Jun) and regulatory protein (CBP, p300, TAFII250, and polymerase II) binding at both the upstream and downstream promoters. Consistent with this observation, we found that the downstream promoter was transcriptionally active, suggesting that the two promoters are functionally equivalent. We also detected asymmetrical binding of histone deacetylases (HDAC-1, -2, and -3) at both promoters. All three HDACs strongly repressed Tax transactivation, and this repression correlated with displacement of Tax from the HTLV-1 promoter. These effects were reciprocal, as Tax expression reversed HDAC repression and displaced HDACs from the HTLV-1 promoter. These data suggest that HTLV-1 transcriptional regulation at both the 5′ and 3′ LTRs is mediated, in part, through the mutually exclusive binding of Tax and HDACs at the proviral promoters.
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Ghosh, SK, JT Abrams, H. Terunuma, EC Vonderheid, and E. DeFreitas. "Human T-cell leukemia virus type I tax/rex DNA and RNA in cutaneous T- cell lymphoma." Blood 84, no. 8 (October 15, 1994): 2663–71. http://dx.doi.org/10.1182/blood.v84.8.2663.2663.
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Abstract Peripheral blood mononuclear cells (PBMCs) and T-cell lines from patients with Sezary syndrome (SS) and skin lesions from patients with mycosis fungoides (MF) were examined by polymerase chain reaction (PCR) for DNA sequences homologous to the human retroviruses human T- lymphotropic virus (HTLV)-I and -II. Results obtained using primers and probes from the tax/rex region of HTLV-I indicate that 72% (18/25) of SS patients PBMCs, 80% (20/25) of T-cell lines established from SS- PBMC, and 30% (3/10) of skin lesions from MF patients were positive for HTLV-I tax/rex region DNA. Sequence analysis of the 127-bp fragment amplified by the tax/rex primers from 4 of these individuals was found to be identical to that in prototypic HTLV-I. Negative results were obtained using primers and probes from the HTLV-I gag region and the HTLV-II gag and tax regions. No PCR products were obtained using all primers and probes using DNA from 9 healthy blood donors and 10 cord bloods. Expression of HTLV-I tax/rex mRNA was found in 4 of 8 Sezary patients, as determined by RNA-PCR, indicating that this viral region is being transcribed in vivo. Exposure to Tax/Rex protein in SS- patients is supported by the fact that serum antibodies against p27rex and p40tax was observed in 43% and 29% of these SS patients, respectively. Although the causal relationship between the HTLV-I tax/rex region and cutaneous T-cell lymphoma (CTCL) remains unclear, these findings support the presence of a truncated HTLV-I retrovirus in CTCL patients.
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Ghosh, SK, JT Abrams, H. Terunuma, EC Vonderheid, and E. DeFreitas. "Human T-cell leukemia virus type I tax/rex DNA and RNA in cutaneous T- cell lymphoma." Blood 84, no. 8 (October 15, 1994): 2663–71. http://dx.doi.org/10.1182/blood.v84.8.2663.bloodjournal8482663.
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Peripheral blood mononuclear cells (PBMCs) and T-cell lines from patients with Sezary syndrome (SS) and skin lesions from patients with mycosis fungoides (MF) were examined by polymerase chain reaction (PCR) for DNA sequences homologous to the human retroviruses human T- lymphotropic virus (HTLV)-I and -II. Results obtained using primers and probes from the tax/rex region of HTLV-I indicate that 72% (18/25) of SS patients PBMCs, 80% (20/25) of T-cell lines established from SS- PBMC, and 30% (3/10) of skin lesions from MF patients were positive for HTLV-I tax/rex region DNA. Sequence analysis of the 127-bp fragment amplified by the tax/rex primers from 4 of these individuals was found to be identical to that in prototypic HTLV-I. Negative results were obtained using primers and probes from the HTLV-I gag region and the HTLV-II gag and tax regions. No PCR products were obtained using all primers and probes using DNA from 9 healthy blood donors and 10 cord bloods. Expression of HTLV-I tax/rex mRNA was found in 4 of 8 Sezary patients, as determined by RNA-PCR, indicating that this viral region is being transcribed in vivo. Exposure to Tax/Rex protein in SS- patients is supported by the fact that serum antibodies against p27rex and p40tax was observed in 43% and 29% of these SS patients, respectively. Although the causal relationship between the HTLV-I tax/rex region and cutaneous T-cell lymphoma (CTCL) remains unclear, these findings support the presence of a truncated HTLV-I retrovirus in CTCL patients.
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Younis, Ihab, Lyne Khair, Miroslav Dundr, Michael D. Lairmore, Genoveffa Franchini, and Patrick L. Green. "Repression of Human T-Cell Leukemia Virus Type 1 and Type 2 Replication by a Viral mRNA-Encoded Posttranscriptional Regulator." Journal of Virology 78, no. 20 (October 15, 2004): 11077–83. http://dx.doi.org/10.1128/jvi.78.20.11077-11083.2004.
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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are complex retroviruses that persist in the host, eventually causing leukemia and neurological disease in a small percentage of infected individuals. In addition to structural and enzymatic proteins, HTLV encodes regulatory (Tax and Rex) and accessory (open reading frame I and II) proteins. The viral Tax and Rex proteins positively regulate virus production. Tax activates viral and cellular transcription to promote T-cell growth and, ultimately, malignant transformation. Rex acts posttranscriptionally to facilitate cytoplasmic expression of viral mRNAs that encode the structural and enzymatic gene products, thus positively controlling virion expression. Here, we report that both HTLV-1 and HTLV-2 have evolved accessory genes to encode proteins that act as negative regulators of both Tax and Rex. HTLV-1 p30II and the related HTLV-2 p28II inhibit virion production by binding to and retaining tax/rex mRNA in the nucleus. Reduction of viral replication in a cell carrying the provirus may allow escape from immune recognition in an infected individual. These data are consistent with the critical role of these proteins in viral persistence and pathogenesis in animal models of HTLV-1 and HTLV-2 infection.
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Endo, Keiichi, Akira Hirata, Kousuke Iwai, Mamoru Sakurai, Masaya Fukushi, Masayasu Oie, Masaya Higuchi, William W. Hall, Fumitake Gejyo, and Masahiro Fujii. "Human T-Cell Leukemia Virus Type 2 (HTLV-2) Tax Protein Transforms a Rat Fibroblast Cell Line but Less Efficiently than HTLV-1 Tax." Journal of Virology 76, no. 6 (March 15, 2002): 2648–53. http://dx.doi.org/10.1128/jvi.76.6.2648-2653.2002.
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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are retroviruses with similar biological properties. Whereas HTLV-1 is the causative agent of an aggressive T-cell leukemia, HTLV-2 has been associated with only a few cases of lymphoproliferative disorders. Tax1 and Tax2 are the transcriptional activators of HTLV-1 and HTLV-2, respectively. Here we show that Tax2 transformed a Rat-1 fibroblast cell line to form colonies in soft agar, but the size and number of the colonies were lower than those of Tax1. Use of a chimeric Tax protein showed that the C-terminal amino acids 300 to 353 were responsible for the high transforming activity of Tax1. Activation of cellular genes by Tax1 through transcription factor NF-κB is reportedly essential for the transformation of Rat-1 cells. Tax2 also activated the transcription through NF-κB in Rat-1 cells, and such activity was equivalent to that induced by Tax1. Thus, the high transforming activity of Tax1 is mediated by mechanisms other than NF-κB activation. Our results showed that Tax2 has a lower transforming activity than Tax1 and suggest that the high transforming activity of Tax1 is involved in the leukemogenic property of HTLV-1.
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Kucerova, Lucia, Veronika Altanerova, Cestmir Altaner, and Kathleen Boris-Lawrie. "Bovine Leukemia Virus Structural Gene Vectors Are Immunogenic and Lack Pathogenicity in a Rabbit Model." Journal of Virology 73, no. 10 (October 1, 1999): 8160–66. http://dx.doi.org/10.1128/jvi.73.10.8160-8166.1999.
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ABSTRACT Infection with a replication-competent bovine leukemia virus structural gene vector (BLV SGV) is an innovative vaccination approach to prevent disease by complex retroviruses. Previously we developed BLV SGV that constitutively expresses BLV gag, pol, and env and related cis-acting sequences but lacks tax, rex, RIII, andGIV and most of the BLV long terminal repeat sequences, including the cis-acting Tax and Rex response elements. The novel SGV virus is replication competent and replicates a selectable vector to a titer similar to that of the parental BLV in cell culture. The overall goal of this study was to test the hypothesis that infection with BLV SGV is nonpathogenic in rabbits. BLV infection of rabbits by inoculation of cell-free BLV or cell-associated BLV typically causes an immunodeficiency-like syndrome and death by 1 year postinfection. We sought to evaluate whether in vivo transfection of BLV provirus recapitulates pathogenic BLV infection and to compare BLV and BLV SGV with respect to infection, immunogenicity, and clinical outcome. Three groups of rabbits were subjected to in vivo transfection with BLV, BLV SGV, or negative control DNA. The results of our 20-month study indicate that in vivo transfection of rabbits with BLV recapitulates the fatal BLV infection produced by cell-free or cell-associated BLV. The BLV-infected rabbits exhibited sudden onset of clinical decline and immunodeficiency-like symptoms that culminated in death. BLV and BLV SGV infected peripheral blood mononuclear cells and induced similar levels of seroconversion to BLV structural proteins. However, BLV SGV exhibited a reduced proviral load and did not trigger the immunodeficiency-like syndrome. These results are consistent with the hypothesis that BLV SGV is infectious and immunogenic and lacks BLV pathogenicity in rabbits, and they support the use of this modified proviral vector delivery system for vaccines against complex retroviruses like BLV.
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Arnold, Joshua, Brenda Yamamoto, Min Li, Andrew J. Phipps, Ihab Younis, Michael D. Lairmore, and Patrick L. Green. "Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1." Blood 107, no. 10 (May 15, 2006): 3976–82. http://dx.doi.org/10.1182/blood-2005-11-4551.
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Natural antisense viral transcripts have been recognized in retroviruses, including human T-cell leukemia virus type 1 (HTLV-1), HIV-1, and feline immunodeficiency virus (FIV), and have been postulated to encode proteins important for the infection cycle and/or pathogenesis of the virus. The antisense strand of the HTLV-1 genome encodes HBZ, a novel nuclear basic region leucine zipper (b-ZIP) protein that in overexpression assays down-regulates Tax oncoprotein-induced viral transcription. Herein, we investigated the contribution of HBZ to HTLV-1–mediated immortalization of primary T lymphocytes in vitro and HTLV-1 infection in a rabbit animal model. HTLV-1 HBZ mutant viruses were generated and evaluated for viral gene expression, protein production, and immortalization capacity. Biologic properties of HBZ mutant viruses in vitro were indistinguishable from wild-type HTLV-1, providing the first direct evidence that HBZ is dispensable for viral replication and cellular immortalization. Rabbits inoculated with irradiated cells expressing HTLV-1 HBZ mutant viruses became persistently infected. However, these rabbits displayed a decreased antibody response to viral gene products and reduced proviral copies in peripheral blood mononuclear cells (PBMCs) as compared with wild-type HTLV-1–infected animals. Our findings indicated that HBZ was not required for in vitro cellular immortalization, but enhanced infectivity and persistence in inoculated rabbits. This study demonstrates that retroviruses use negative-strand–encoded proteins in the establishment of chronic viral infections.
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Goldberg, Tony L., David M. Sintasath, Colin A. Chapman, Kenneth M. Cameron, William B. Karesh, Shaohua Tang, Nathan D. Wolfe, Innocent B. Rwego, Nelson Ting, and William M. Switzer. "Coinfection of Ugandan Red Colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) with Novel, Divergent Delta-, Lenti-, and Spumaretroviruses." Journal of Virology 83, no. 21 (August 19, 2009): 11318–29. http://dx.doi.org/10.1128/jvi.02616-08.
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ABSTRACT Nonhuman primates host a plethora of potentially zoonotic microbes, with simian retroviruses receiving heightened attention due to their roles in the origins of human immunodeficiency viruses type 1 (HIV-1) and HIV-2. However, incomplete taxonomic and geographic sampling of potential hosts, especially the African colobines, has left the full range of primate retrovirus diversity unexplored. Blood samples collected from 31 wild-living red colobus monkeys (Procolobus [Piliocolobus] rufomitratus tephrosceles) from Kibale National Park, Uganda, were tested for antibodies to simian immunodeficiency virus (SIV), simian T-cell lymphotrophic virus (STLV), and simian foamy virus (SFV) and for nucleic acids of these same viruses using genus-specific PCRs. Of 31 red colobus tested, 22.6% were seroreactive to SIV, 6.4% were seroreactive to STLV, and 97% were seroreactive to SFV. Phylogenetic analyses of SIV polymerase (pol), STLV tax and long terminal repeat (LTR), and SFV pol and LTR sequences revealed unique SIV and SFV strains and a novel STLV lineage, each divergent from corresponding retroviral lineages previously described in Western red colobus (Procolobus badius badius) or black-and-white colobus (Colobus guereza). Phylogenetic analyses of host mitochondrial DNA sequences revealed that red colobus populations in East and West Africa diverged from one another approximately 4.25 million years ago. These results indicate that geographic subdivisions within the red colobus taxonomic complex exert a strong influence on retroviral phylogeny and that studying retroviral diversity in closely related primate taxa should be particularly informative for understanding host-virus coevolution.
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Easley, Rebecca, Lawrence Carpio, Irene Guendel, Zachary Klase, Soyun Choi, Kylene Kehn-Hall, John N. Brady, and Fatah Kashanchi. "Human T-Lymphotropic Virus Type 1 Transcription and Chromatin-Remodeling Complexes." Journal of Virology 84, no. 9 (February 17, 2010): 4755–68. http://dx.doi.org/10.1128/jvi.00851-09.
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ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) encodes the viral protein Tax, which is believed to act as a viral transactivator through its interactions with a variety of transcription factors, including CREB and NF-κB. As is the case for all retroviruses, the provirus is inserted into the host DNA, where nucleosomes are deposited to ensure efficient packaging. Nucleosomes act as roadblocks in transcription, making it difficult for RNA polymerase II (Pol II) to proceed toward the 3′ end of the genome. Because of this, a variety of chromatin remodelers can act to modify nucleosomes, allowing for efficient transcription. While a number of covalent modifications are known to occur on histone tails in HTLV-1 infection (i.e., histone acetyltransferases [HATs], histone deacetylases [HDACs], and histone methyltransferases [HMTs]), evidence points to the use of chromatin remodelers that use energy from ATP hydrolysis to remodel nucleosomes. Here we confirm that BRG1, which is the core subunit of eight chromatin-remodeling complexes, is essential not only for Tax transactivation but also for viral replication. This is especially evident when wild-type infectious clones of HTLV-1 are used. BRG1 associates with Tax at the HTLV-1 long terminal repeat (LTR), and coexpression of BRG1 and Tax results in increased rates of transcription. The interaction of BRG1 with Tax additionally recruits the basal transcriptional machinery and removes some of the core histones from the nucleosome at the start site (Nuc 1). When using the BRG1-deficient cell lines SW13, C33A, and TSUPR1, we observed little viral transcription and no viral replication. Importantly, while these three cell lines do not express detectable levels of BRG1, much of the SWI/SNF complex remains assembled in the cells. Knockdown of BRG1 and associated SWI/SNF subunits suggests that the BRG1-utilizing SWI/SNF complex PBAF is responsible for HTLV-1 nucleosome remodeling. Finally, HTLV-1 infection of cell lines with a knockdown in BRG1 or the PBAF complex results in a significant reduction in viral production. Overall, we concluded that BRG1 is required for Tax transactivation and HTLV-1 viral production and that the PBAF complex appears to be responsible for nucleosome remodeling.
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Ye, Jianxin, Li Xie, and Patrick L. Green. "Tax and Overlapping Rex Sequences Do Not Confer the Distinct Transformation Tropisms of Human T-Cell Leukemia Virus Types 1 and 2." Journal of Virology 77, no. 14 (July 15, 2003): 7728–35. http://dx.doi.org/10.1128/jvi.77.14.7728-7735.2003.
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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are distinct oncogenic retroviruses that infect several cell types but display their biological and pathogenic activity only in T cells. Previous studies have indicated that in vivo HTLV-1 has a preferential tropism for CD4+ T cells, whereas HTLV-2 in vivo tropism is less clear but appears to favor CD8+ T cells. Both CD4+ and CD8+ T cells are susceptible to HTLV-1 and HTLV-2 infection in vitro, and HTLV-1 has a preferential immortalization and transformation tropism of CD4+ T cells, whereas HTLV-2 immortalizes and transforms primarily CD8+ T cells. The molecular mechanism that determines this tropism of HTLV-1 and HTLV-2 has not been determined. HTLV-1 and HTLV-2 carry the tax and rex transregulatory genes in separate but partially overlapping reading frames. Since Tax has been shown to be critical for cellular transformation in vitro and interacts with numerous cellular processes, we hypothesized that the viral determinant of transformation tropism is encoded by tax. Using molecular clones of HTLV-1 (Ach) and HTLV-2 (pH6neo), we constructed recombinants in which tax and overlapping rex genes of the two viruses were exchanged. p19 Gag expression from proviral clones transfected into 293T cells indicated that both recombinants contained functional Tax and Rex but with significantly altered activity compared to the wild-type clones. Stable transfectants expressing recombinant viruses were established, irradiated, and cocultured with peripheral blood mononuclear cells. Both recombinants were competent to transform T lymphocytes with an efficiency similar to that of the parental viruses. Flow cytometry analysis indicated that HTLV-1 and HTLV-1/TR2 had a preferential tropism for CD4+ T cells and that HTLV-2 and HTLV-2/TR1 had a preferential tropism for CD8+ T cells. Our results indicate that tax/rex in different genetic backgrounds display altered functional activity but ultimately do not contribute to the different in vitro transformation tropisms. This first study with recombinants between HTLV-1 and HTLV-2 is the initial step in elucidating the different pathobiologies of HTLV-1 and HTLV-2.
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Yin, Han, Priya Kannian, Nathan Dissinger, Robyn Haines, Stefan Niewiesk, and Patrick L. Green. "Human T-Cell Leukemia Virus Type 2 Antisense Viral Protein 2 Is Dispensable forIn VitroImmortalization but Functions To Repress Early Virus ReplicationIn Vivo." Journal of Virology 86, no. 16 (May 23, 2012): 8412–21. http://dx.doi.org/10.1128/jvi.00717-12.
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Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are closely related but pathogenically distinct human retroviruses. The antisense strand of the HTLV-1 genome encodes HTLV-1 basic leucine zipper (b-ZIP) protein (HBZ), a protein that inhibits Tax-mediated viral transcription, enhances T-cell proliferation, and promotes viral persistence. Recently, an HTLV-2 antisense viral protein (APH-2) was identified. Despite its lack of a typical b-ZIP domain, APH-2, like HBZ, interacts with cyclic AMP response element binding protein (CREB) and downregulates Tax-mediated viral transcription. Here, we provide evidence that the APH-2 C-terminal LXXLL motif is important for CREB binding and Tax repression. In order to investigate the functional role of APH-2 in the HTLV-2-mediated immortalization of primary T lymphocytesin vitroand in HTLV-2 infectionin vivo, we generated APH-2 mutant viruses. In cell cultures, the immortalization capacities of APH-2 mutant viruses were indistinguishable from that of wild-type HTLV-2 (wtHTLV-2), indicating that, like HBZ, APH-2 is dispensable for viral infection and cellular transformation.In vivo, rabbits inoculated with either wtHTLV-2 or APH-2 mutant viruses established a persistent infection. However, the APH-2 knockout virus displayed an increased replication rate, as measured by an increased viral antibody response and a higher proviral load. In contrast to HTLV-1 HBZ, we show that APH-2 is dispensable for the establishment of an efficient infection and persistence in a rabbit animal model. Therefore, antisense proteins of HTLV-1 and HTLV-2 have evolved different functionsin vivo, and further comparative studies will provide fundamental insights into the distinct pathobiologies of these two viruses.
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Panfil, Amanda R., Nathan J. Dissinger, Cory M. Howard, Brandon M. Murphy, Kristina Landes, Soledad A. Fernandez, and Patrick L. Green. "Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis." Journal of Virology 90, no. 7 (January 27, 2016): 3760–72. http://dx.doi.org/10.1128/jvi.03113-15.
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ABSTRACTHuman T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that transform T cellsin vitrobut have distinct pathological outcomesin vivo. HTLV-1 encodes a protein from the antisense strand of its proviral genome, the HTLV-1 basic leucine zipper factor (HBZ), which inhibits Tax-1-mediated viral transcription and promotes cell proliferation, a high proviral load, and persistencein vivo. In adult T-cell leukemia/lymphoma (ATL) cell lines and patient T cells,hbzis often the only viral gene expressed. The antisense strand of the HTLV-2 proviral genome also encodes a protein termed APH-2. Like HBZ, APH-2 is able to inhibit Tax-2-mediated viral transcription and is detectable in most primary lymphocytes from HTLV-2-infected patients. However, unlike HBZ, the loss of APH-2in vivoresults in increased viral replication and proviral loads, suggesting that HBZ and APH-2 modulate the virus and cellular pathways differently. Herein, we examined the effect of APH-2 on several known HBZ-modulated pathways: NF-κB (p65) transactivation, transforming growth factor β (TGF-β) signaling, and interferon regulatory factor 1 (IRF-1) transactivation. Like HBZ, APH-2 has the ability to inhibit p65 transactivation. Conversely, HBZ and APH-2 have divergent effects on TGF-β signaling and IRF-1 transactivation. Quantitative PCR and protein half-life experiments revealed a substantial disparity between HBZ and APH-2 transcript levels and protein stability, respectively. Taken together, our data further elucidate the functional differences between HBZ and APH-2 and how these differences can have profound effects on the survival of infected cells and, ultimately, pathogenesis.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are highly related retroviruses that have distinct pathological outcomes in infected hosts. Functional comparisons of HTLV-1 and HTLV-2 proteins provide a better understanding about how HTLV-1 infection is associated with disease and HTLV-2 infection is not. The HTLV genome antisense-strand geneshbzandaph-2are often the only viral genes expressed in HTLV-infected T cells. Previously, our group found that HTLV-1 HBZ and HTLV-2 APH-2 had distinct effectsin vivoand hypothesized that the differences in the interactions of HBZ and APH-2 with important cell signaling pathways dictate whether cells undergo proliferation, apoptosis, or senescence. Ultimately, these functional differences may affect how HTLV-1 causes disease but HTLV-2 generally does not. In the current study, we compared the effects of HBZ and APH-2 on several HTLV-relevant cellular pathways, including the TGF-β signaling, NF-κB activation, and IRF-1 transactivation pathways.
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Albrecht, Björn, and Michael D. Lairmore. "Critical Role of Human T-Lymphotropic Virus Type 1 Accessory Proteins in Viral Replication and Pathogenesis." Microbiology and Molecular Biology Reviews 66, no. 3 (September 2002): 396–406. http://dx.doi.org/10.1128/mmbr.66.3.396-406.2002.
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SUMMARY Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with a diverse range of lymphoproliferative and neurodegenerative diseases, yet pathogenic mechanisms induced by the virus remain obscure. This complex retrovirus contains typical structural and enzymatic genes but also unique regulatory and accessory genes in four open reading frames (ORFs) of the pX region of the viral genome (pX ORFs I to IV). The regulatory proteins encoded by pX ORFs III and IV, Tax and Rex, respectively, have been extensively characterized. In contrast the contribution of the four accessory proteins p12I, p27I, p13II, and p30II, encoded by pX ORFs I and II, to viral replication and pathogenesis remained unclear. Proviral clones that are mutated in either pX ORF I or II, while fully competent in cell culture, are severely limited in their replicative capacity in a rabbit model. Emerging evidence indicates that the HTLV-1 accessory proteins are critical for establishment of viral infectivity, enhance T-lymphocyte activation, and potentially alter gene transcription and mitochondrial function. HTLV-1 pX ORF I expression is critical to the viral infectivity in resting primary lymphocytes, suggesting a role for p12I in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12I, encoded from pX ORF I, activates NFAT, a key T-cell transcription factor, through calcium-mediated signaling pathways and may lower the threshold of lymphocyte activation via the JAK/STAT pathway. In contrast p30II localizes to the nucleus and represses viral promoter activity, but may regulate cellular gene expression through p300/CBP or related coactivators of transcription. p13II targets mitochondrial proteins, where it alters the organelle morphology and may influence energy metabolism. Collectively, studies of the molecular functions of the HTLV-1 accessory proteins provide insight into strategies used by retroviruses that are associated with lymphoproliferative diseases.
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Xiao, Jianqiao, and Gertrude C. Buehring. "In Vivo Protein Binding and Functional Analysis ofcis-Acting Elements in the U3 Region of the Bovine Leukemia Virus Long Terminal Repeat." Journal of Virology 72, no. 7 (July 1, 1998): 5994–6003. http://dx.doi.org/10.1128/jvi.72.7.5994-6003.1998.
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ABSTRACT Bovine leukemia virus (BLV) is a member of the human T-cell leukemia virus (HTLV)/BLV group of retroviruses. These viruses regulate their own transcription by producing Tax, a protein which activates the virus promoter region, the long terminal repeat (LTR). To explore the molecular mechanisms involved in the transactivation, we identified protein binding elements by in vivo footprinting and analyzed their function by site- directed mutagenesis. We used in vivo dimethyl sulfate footprinting by ligation-mediated PCR to detect constitutive in vivo protein-DNA interactions in a BLV-producing cell line, Bat2Cl6. The U3 region and part of the R region of the LTR were footprinted. In addition to the cis-acting elements (three cyclic AMP-responsive elements [CREs] and two AP4 sites) reported by others to be important for Tax-mediated activation of the BLV LTR, we found footprints in regions flanking these elements and in the core promoter region. The importance of these sites for transcriptional activation was studied by site-directed mutagenesis followed by promoter function analysis of the mutants with a chloramphenicol acetyltransferase reporter system. Our data corroborate those of others showing that the CREs are necessary for transactivation of the LTR, and they identify two new functional sites not previously reported by others. We show that the middle region of the BLV U3 contains multiple dual-functioning cis-acting elements which act as either positive or negative regulatory elements depending on the cell type tested. This is the first report of a functional mapping of the cis-acting elements of a virus of the HTLV/BLV group.
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Halbrook, Megan, Adva Gadoth, Anupama Shankar, HaoQiang Zheng, Ellsworth M. Campbell, Nicole A. Hoff, Jean-Jacques Muyembe, Emile Okitolonda Wemakoy, Anne W. Rimoin, and William M. Switzer. "Human T-cell lymphotropic virus type 1 transmission dynamics in rural villages in the Democratic Republic of the Congo with high nonhuman primate exposure." PLOS Neglected Tropical Diseases 15, no. 1 (January 28, 2021): e0008923. http://dx.doi.org/10.1371/journal.pntd.0008923.
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The Democratic Republic of the Congo (DRC) has a history of nonhuman primate (NHP) consumption and exposure to simian retroviruses yet little is known about the extent of zoonotic simian retroviral infections in DRC. We examined the prevalence of human T-lymphotropic viruses (HTLV), a retrovirus group of simian origin, in a large population of persons with frequent NHP exposures and a history of simian foamy virus infection. We screened plasma from 3,051 persons living in rural villages in central DRC using HTLV EIA and western blot (WB). PCR amplification of HTLV tax and LTR sequences from buffy coat DNA was used to confirm infection and to measure proviral loads (pVLs). We used phylogenetic analyses of LTR sequences to infer evolutionary histories and potential transmission clusters. Questionnaire data was analyzed in conjunction with serological and molecular data. A relatively high proportion of the study population (5.4%, n = 165) were WB seropositive: 128 HTLV-1-like, 3 HTLV-2-like, and 34 HTLV-positive but untypeable profiles. 85 persons had HTLV indeterminate WB profiles. HTLV seroreactivity was higher in females, wives, heads of households, and increased with age. HTLV-1 LTR sequences from 109 persons clustered strongly with HTLV-1 and STLV-1 subtype B from humans and simians from DRC, with most sequences more closely related to STLV-1 from Allenopithecus nigroviridis (Allen’s swamp monkey). While 18 potential transmission clusters were identified, most were in different households, villages, and health zones. Three HTLV-1-infected persons were co-infected with simian foamy virus. The mean and median percentage of HTLV-1 pVLs were 5.72% and 1.53%, respectively, but were not associated with age, NHP exposure, village, or gender. We document high HTLV prevalence in DRC likely originating from STLV-1. We demonstrate regional spread of HTLV-1 in DRC with pVLs reported to be associated with HTLV disease, supporting local and national public health measures to prevent spread and morbidity.
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Palker, T. J. "Human T-cell Lymphotropic Viruses: Review and Prospects for Antiviral Therapy." Antiviral Chemistry and Chemotherapy 3, no. 3 (June 1992): 127–39. http://dx.doi.org/10.1177/095632029200300301.
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The human T-cell lymphotropic viruses types I and II (HTLV-I, II) pose challenges to researchers and clinicians who seek to unveil mechanisms of viral transformation and pathogenesis. HTLV-I infection in humans is associated with a wide array of primary and secondary diseases ranging from mild immunosuppression to adult T-cell leukaemia/lymphoma and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurological degenerative syndrome. As retroviruses, HTLV-I and II share similar replicative cycles with human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome. However, in contrast to HIV-I which destroys CD4+ T cells, HTLV-I and II can preferentially transform a CD4+ T-cell subset to an unrestricted growth state. HTLV-I and II, along with simian T-lymphotropic virus (STLV) and bovine leukaemia virus (BLV), form a phylogenetic group which is distinct from ungulate, non-human primate and human lentiviruses such as visna, simian immunodeficiency virus (SIV), and human immunodeficiency viruses types 1 and 2. The proviral genome of HTLV-I is flanked at the 5′ and 3′ ends by long terminal repeats (LTR) and is further subdivided into structural gag and env genes, a pro gene encoding an aspartyl protease, a pol gene which encodes reverse transcriptase and endonuclease, and the regulatory gene elements tax and rex. Regions within the LTR contain recognition sites for cellular proteins and the tax gene product that collectively promote viral expression. Tax-mediated activation of cellular genes involved in growth and differentiation is suspected to play a dominant role in the leukaemogenic process associated with HTLV-I infection. Differential rex-regulated splicing of viral message gives rise to transcripts encoding the polyprotein precursor gag-pro-pol (unspliced), envelope (single spliced), or tax/rex (doubly spliced). The 100nm HTLV virion contains an electron-dense core surrounding a divalent-single stranded DNA genome. This core is in turn enclosed by concentric shells of matrix protein and an outer lipid bilayer, the latter acquired as the virus buds from the surface of the infected cell. Envelope glycoproteins associated with the outside of this lipid bilayer can interact with viral receptors on cells and mediate virus entry. Antiviral strategies have been directed at inhibiting viral entry into cells (sulphated and non-sulphated polysaccharides, vaccines), blocking of viral replication (AZT, suramin), intracellular immunization (transdominant repression of rex), and elimination of virus infected cells (IL-2 receptor-directed toxins). Serological screening of the blood supply and curtailing breast feeding of children by HTLV-I + mothers have likely had a major impact in preventing HTLV-I infection.
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Paca, Robert E., Robert A. Ogert, Catherine S. Hibbert, Elisa Izaurralde, and Karen L. Beemon. "Rous Sarcoma Virus DR Posttranscriptional Elements Use a Novel RNA Export Pathway." Journal of Virology 74, no. 20 (October 15, 2000): 9507–14. http://dx.doi.org/10.1128/jvi.74.20.9507-9514.2000.
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ABSTRACT Rous sarcoma virus (RSV), a simple retrovirus, needs to export unspliced viral RNA from the nucleus to the cytoplasm, circumventing the host cell restriction on cytoplasmic expression of intron-containing RNA. The cytoplasmic accumulation of full-length viral RNA is promoted by two cis-acting direct repeat (DR) elements that flank the src gene; at least one copy of the DR sequence is necessary for viral replication. We show here that the DR mediates export of a reporter construct from the nucleus, suggesting it is a constitutive transport element (CTE). In contrast, human immunodeficiency virus type 1 (HIV-1) and other complex retroviruses encode accessory proteins, Rev or Rex, which promote export of incompletely spliced viral transcripts. This RNA export pathway is CRM1 dependent and can be blocked by the cytotoxic agent leptomycin B. We show here that DR-mediated export is CRM1 independent, suggesting that RSV uses a different export pathway from that of HIV-1 and other complex retroviruses. The simian retroviruses have a CTE which interacts with the cellular Tap export protein. However, we were unable to detect binding of the RSV DR RNA to Tap, suggesting it may use a different export pathway from that of the simian retroviruses. These data suggest that the RSV DR element uses a novel nucleocytoplasmic export pathway.
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Merezak, C., C. Pierreux, E. Adam, F. Lemaigre, G. G. Rousseau, C. Calomme, C. Van Lint, et al. "Suboptimal Enhancer Sequences Are Required for Efficient Bovine Leukemia Virus Propagation In Vivo: Implications for Viral Latency." Journal of Virology 75, no. 15 (August 1, 2001): 6977–88. http://dx.doi.org/10.1128/jvi.75.15.6977-6988.2001.
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ABSTRACT Repression of viral expression is a major strategy developed by retroviruses to escape from the host immune response. The absence of viral proteins (or derived peptides) at the surface of an infected cell does not permit the establishment of an efficient immune attack. Such a strategy appears to have been adopted by animal oncoviruses such as bovine leukemia virus (BLV) and human T-cell leukemia virus (HTLV). In BLV-infected animals, only a small fraction of the infected lymphocytes (between 1 in 5,000 and 1 in 50,000) express large amounts of viral proteins; the vast majority of the proviruses are repressed at the transcriptional level. Induction of BLV transcription involves the interaction of the virus-encoded Tax protein with the CREB/ATF factors; the resulting complex is able to interact with three 21-bp Tax-responsive elements (TxRE) located in the 5′ long terminal repeat (5′ LTR). These TxRE contain cyclic AMP-responsive elements (CRE), but, remarkably, the “TGACGTCA” consensus is never strictly conserved in any viral strain (e.g.,AGACGTCA, TGACGGCA, TGACCTCA). To assess the role of these suboptimal CREs, we introduced a perfect consensus sequence within the TxRE and showed by gel retardation assays that the binding efficiency of the CREB/ATF proteins was increased. However,trans-activation of a luciferase-based reporter by Tax was not affected in transient transfection assays. Still, in the absence of Tax, the basal promoter activity of the mutated LTR was increased as much as 20-fold. In contrast, mutation of other regulatory elements within the LTR (the E box, NF-κB, and glucocorticoid- or interferon-responsive sites [GRE or IRF]) did not induce a similar alteration of the basal transcription levels. To evaluate the biological relevance of these observations made in vitro, the mutations were introduced into an infectious BLV molecular clone. After injection into sheep, it appeared that all the recombinants were infectious in vivo and did not revert into a wild-type virus. All of them, except one, propagated at wild-type levels, indicating that viral spread was not affected by the mutation. The sole exception was the CRE mutant; proviral loads were drastically reduced in sheep infected with this type of virus. We conclude that a series of sites (NF-κB, IRF, GRE, and the E box) are not required for efficient viral spread in the sheep model, although mutation of some of these motifs might induce a minor phenotype during transient transfection assays in vitro. Remarkably, a provirus (pBLV-Δ21-bp) harboring only two TxRE was infectious and propagated at wild-type levels. And, most importantly, reconstitution of a consensus CRE, within the 21-bp enhancers increases binding of CREB/ATF proteins but abrogates basal repression of LTR-directed transcription in vitro. Suboptimal CREs are, however, essential for efficient viral spread within infected sheep, although these sites are dispensable for infectivity. These results suggest an evolutionary selection of suboptimal CREs that repress viral expression with escape from the host immune response. These observations, which were obtained in an animal model for HTLV-1, are of interest for oncovirus-induced pathogenesis in humans.
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Elaiw, A. M., and N. H. AlShamrani. "Modeling and stability analysis of HIV/HTLV-I co-infection." International Journal of Biomathematics 14, no. 05 (March 11, 2021): 2150030. http://dx.doi.org/10.1142/s1793524521500303.
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Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that infect the susceptible CD[Formula: see text]T cells. It is known that HIV and HTLV-I have in common a way of transmission through direct contact with certain body fluids related to infected individuals. Therefore, it is not surprising that a mono-infected person with one of these viruses can be co-infected with the other virus. In the literature, a great number of mathematical models has been presented to describe the within-host dynamics of HIV or HTLV-I mono-infection. However, the within-host dynamics of HIV/HTLV-I co-infection has not been modeled. In this paper, we develop a new within-host HIV/HTLV-I co-infection model. The model includes the impact of Cytotoxic T lymphocytes (CTLs) immune response, which is important to control the progression of viral co-infection. The model describes the interaction between susceptible CD[Formula: see text]T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. We first show the nonnegativity and boundedness of the model’s solutions and then we calculate all possible equilibria. We derive the threshold parameters which govern the existence and stability of all equilibria of the model. We prove the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle’s invariance principle. We have presented numerical simulations to illustrate the effectiveness of our main results. In addition, we discuss the effect of HTLV-I infection on the HIV-infected patients and vice versa.
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Cockerell, GL, J. Rovnak, PL Green, and IS Chen. "A deletion in the proximal untranslated pX region of human T-cell leukemia virus type II decreases viral replication but not infectivity in vivo." Blood 87, no. 3 (February 1, 1996): 1030–35. http://dx.doi.org/10.1182/blood.v87.3.1030.bloodjournal8731030.
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The function of untranslated (UT) nucleotide sequences in the proximal portion of the pX region of the human T-cell leukemia virus (HTLV) family of retroviruses remains enigmatic. Previous studies have shown that these sequences are not necessary for the expression of viral proteins or for the induction, transmission, or maintenance of the transformed cell type in vitro. To determine the effect of the UT region in vivo, separate groups of rabbits were inoculated with lethally irradiated, stable clones of the human B-lymphoblastoid cell line, 729, transfected with either a full-length wild-type HTLV-II clone (pH6neo) or a mutant clone containing a 324-bp deletion in the proximal UT portion of pX (pH6neo delta UT[6661–6984]), or nontransfected 729 cells. All rabbits inoculated with either wild-type or pX-deleted HTLV-II developed a similar profile and titer of serum antibodies against HTLV-II antigens, as determined by Western immunoblots, by 4 weeks postinoculation (PI). Antibody titers, as determined by enzyme immunoassay, were similar between the two groups of rabbits and increased over the 18-week period of study. All rabbits were killed at 18 weeks PI, and spleen, peripheral blood lymphocytes (PBMC), bone marrow, and mesenteric lymph node were assayed for HTLV-II tax/rex sequences by quantitative polymerase chain reaction. Virus was detected in all tissues tested from all rabbits inoculated with 729pH6neo cells containing wild-type HTLV-II, which contained between 1.4 and 0.3 mean copies of provirus per cell. In contrast, the distribution and number of provirus copies were more limited in rabbits inoculated with 729pH6neo delta UT(6661–6984) cells containing UT- deleted HTLV-II; in most tissues, there was a fivefold to sevenfold reduction in mean provirus copies per cell as compared with rabbits inoculated with wild-type HTLV-II. All rabbits inoculated with control 729 cells remained negative for HTLV-II infection, as determined by the same techniques. It was concluded that UT sequences in the proximal portion of HTLV-II are not necessary for infection but confer increased replicative capacity in vivo.
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Lecellier, Charles-Henri, Manuel Neves, Marie-Lou Giron, Joelle Tobaly-Tapiero, and Ali Saïb. "Further Characterization of Equine Foamy Virus Reveals Unusual Features among the Foamy Viruses." Journal of Virology 76, no. 14 (July 15, 2002): 7220–27. http://dx.doi.org/10.1128/jvi.76.14.7220-7227.2002.
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ABSTRACT Foamy viruses (FVs) are nonpathogenic, widely spread complex retroviruses which have been isolated in nonhuman primates, cattle, cats, and more recently in horses. The equine foamy virus (EFV) was isolated from healthy horses and was characterized by molecular cloning and nucleotide sequence analysis. Here, to further characterize this new FV isolate, the location of the transcriptional cap and poly(A) addition sites as well as the main splice donor and acceptor sites were determined, demonstrating the existence of the specific subgenomic pol mRNA, one specific feature of FVs. Moreover, similar to what has been described for the human foamy virus (HFV), the prototype of FVs, a replication-defective EFV genome was identified during persistent infection. At the protein level, the use of specific antibodies allowed us to determine the size and the subcellular localization of EFV Gag, Env, and Tas, the viral transactivators. While EFV Gag was detected in both the cytoplasm and the nucleus, EFV Env mainly localized in the Golgi complex, in contrast to HFV Env, which is sequestered in the endoplasmic reticulum. In addition, electron microscopy analysis demonstrated that EFV budding occurs at the plasma membrane and not intracellularly, as is the case for primate FVs. Interestingly, EFV Tas was detected both in the nucleus and the cytoplasm of Tas-transfected cells, in contrast to the strict nuclear localization of other FV Tas but similar to the equine infectious anemia virus Tat gene product. Taken together, our results reveal that this new FV isolate exhibits remarkable features among FVs, bringing new insights into the biology of these unconventional retroviruses.
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Peloponese, Jean-Marie, Junichiro Yasunaga, Takao Kinjo, Koichi Watashi, and Kuan-Teh Jeang. "Peptidylproline cis-trans-Isomerase Pin1 Interacts with Human T-Cell Leukemia Virus Type 1 Tax and Modulates Its Activation of NF-κB." Journal of Virology 83, no. 7 (January 21, 2009): 3238–48. http://dx.doi.org/10.1128/jvi.01824-08.
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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T-cell leukemia (ATL). The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. ATL is a highly virulent cancer that is resistant to chemotherapeutic treatments. To understand this disease better, it is important to comprehend how HTLV-1 promotes cellular growth and survival. Tax activation of NF-κB is important for the proliferation and transformation of virus-infected cells. We show here that prolyl isomerase Pin1 is over expressed in HTLV-1 cell lines; Pin1 binds Tax and regulates Tax-induced NF-κB activation.
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Sheleg, Sergey V., Jean-Marie Peloponese, Ya-Hui Chi, Yan Li, Michael Eckhaus, and Kuan-Teh Jeang. "Evidence for Cooperative Transforming Activity of the Human Pituitary Tumor Transforming Gene and Human T-Cell Leukemia Virus Type 1 Tax." Journal of Virology 81, no. 15 (May 16, 2007): 7894–901. http://dx.doi.org/10.1128/jvi.00555-07.
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ABSTRACT Aneuploidy is frequent in cancers. Recently it was found that pituitary tumor transforming gene (PTTG; also called Pds1p or securin) is overexpressed in many different tumors. Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that primarily infects CD4+ T lymphocytes and causes adult T-cell leukemia. Here, we report that overexpression of human PTTG cooperated with the HTLV-I Tax oncoprotein in cellular transformation. Coexpression of Tax and PTTG enhanced chromosomal instability and neoplastic changes to levels greater than overexpression of either factor singularly. Cells that overexpressed both PTTG and Tax induced tumors more robustly in nude mice than cells that expressed either PTTG alone or Tax alone.
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Asbury, Sarah, Seung Mi Yoo, and Jonathan Bramson. "101 Engineering gamma/delta T cells with the T-Cell antigen coupler receptor effectively induces antigen-specific tumor cytotoxicity in vitro and in vivo." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A112. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0101.
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BackgroundEngineered T cell therapies have revolutionized treatment of relapsed refractory haematological malignancies, however the cost of treatment for autologous products remains a significant challenge to their widespread use. The high cost is driven largely by the need for personalized manufacturing of autologous cell products. A non-conventional class of T cells, the gamma/delta T cell, can be safely transplanted into an unrelated recipient without inducing graft-versus host disease,1 making them an ideal candidate for mass-manufactured off-the-shelf T cell therapies. We have previously described a novel method of directing conventional alpha/beta T cells towards tumour targets by co-opting the T cell receptor using the T cell Antigen Coupler (TAC) receptor.2 Here, we describe the use of TAC receptors to engineer antigen-specific reactivity into gamma/delta T cells, resulting in highly potent anti-tumor cytotoxicity.MethodsEngineered gamma/delta T cells were manufactured by activating PBMCs with Zoledronate and IL-2. The TAC transgene was introduced into T cells using either VSV-G pseudotype lentivirus or GALV-psuedotyped gamma-retrovirus vectors.Through optimization studies, we determined transduction was highest 24 hours post-activation for lentivirus and 72 hours post-activation for gamma-retrovirus. Cultures were fed with IL-2 supplemented media every 2 – 3 days and enriched on Day 14 to >99% gamma/delta T cell purity using CD4/CD8 magnetic-activated cell sorting depletion (Miltenyi Biotec).ResultsBoth methods of gene transfer tested for our pilot study yielded excellent gene transduction (40% - 70%). Using lentivirus-engineered gamma/delta T cells, we demonstrated that the TAC receptor re-directs gamma/delta T cells to attack tumors in an antigen-specific manner. The presence of the TAC receptor did not interfere with lysis of tumor cells via the natural tumor-reactive gamma/delta T cell receptors. Importantly, TAC-engineered gamma/delta T cells displayed robust cytotoxicity at very low effector:target ratios (<1) and caused regression of human tumor xenografts that were otherwise resistant to non-engineered gamma/delta T cells. Curiously, gamma/delta T cell manufacturing was sensitive to the quality of the lentivirus product, where products with low titers were associated with outgrowth of conventional alpha/beta T cells. Outgrowth of alpha/beta T cells was not observed with gamma-retroviruses. We are presently evaluating the anti-tumor activity of gamma-retrovirus-engineered gamma/delta T cells.ConclusionsOff-the-shelf engineered gamma/delta T cells represent a strategy to reduce manufacturing cost and may represent the next generation of engineered T cell therapies.TAC receptors provide a robust tool for directing gamma/delta T cells to attack tumors that are otherwise resistant to gamma/delta T cells and should be evaluated further.AcknowledgementsThis work was supported by the Samuel Family Foundation, the Ontario Centres of Excellence and Triumvira Immunologics.Ethics ApprovalThe study was approved by McMaster’s Animal Research Ethics Board, AUP#19-02-10.ReferencesArruda LCM, Gaballa A, Uhlin M. Impact of γδ T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis. Blood Adv 2019;3(21):3436–3448.Helsen CW, Hammill JA, Lau VWC, et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat Commun 2018;9(1):3049.
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Sandrock, Robert W., Isaac Peterson, Cameron Evans, William Wheatley, and Alexander Kamb. "Enhanced expression of exogenous genes from retroviruses using HIV2/Tat." Journal of Biotechnology 97, no. 1 (July 2002): 41–50. http://dx.doi.org/10.1016/s0168-1656(02)00054-8.
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Foskett, Shannon M., Romi Ghose, Derek Ng Tang, Dorothy E. Lewis, and Andrew P. Rice. "Antiapoptotic Function of Cdk9 (TAK/P-TEFb) in U937 Promonocytic Cells." Journal of Virology 75, no. 3 (February 1, 2001): 1220–28. http://dx.doi.org/10.1128/jvi.75.3.1220-1228.2001.
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ABSTRACT Cdk9 is the catalytic subunit of TAK (cyclinT1/P-TEFb), a cellular protein kinase that mediates human immunodeficiency virus type 1 (HIV-1) Tat transcriptional activation function. To examine Cdk9 function in cells relevant to HIV-1 infection, we used a murine leukemia virus retrovirus vector to transduce and overexpress the cDNA of a dominant negative mutant Cdk9 protein (Cdk9-dn) in Jurkat T cells and U937 promonocytic cells. In Jurkat cells, overexpression of Cdk9-dn specifically inhibited Tat transactivation and HIV-1 replication but had no inhibitory effect on induction of CD69, CD25, and interleukin-2 following T-cell activation. In U937 cells, overexpression of Cdk9-dn sensitized cells to apoptosis, especially after phorbol myristate acetate (PMA) treatment to induce differentiation to macrophage-like cells. Because Cdk9 function is induced in PMA-treated U937 cells, Cdk9 may play an antiapoptotic role during monocyte differentiation.
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Arya, Suresh K., Barbara Beaver, Linda Jagodzinski, Barbara Ensoli, Phyllis J. Kanki, Jan Albert, Eva-Maria Fenyo, et al. "New human and simian HIV-related retroviruses possess functional transactivator (tat) gene." Nature 328, no. 6130 (August 1987): 548–50. http://dx.doi.org/10.1038/328548a0.
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Chiari, Estelle, Isabelle Lamsoul, Julie Lodewick, Cécile Chopin, Françoise Bex, and Claudine Pique. "Stable Ubiquitination of Human T-Cell Leukemia Virus Type 1 Tax Is Required for Proteasome Binding." Journal of Virology 78, no. 21 (November 1, 2004): 11823–32. http://dx.doi.org/10.1128/jvi.78.21.11823-11832.2004.
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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the retrovirus responsible for adult T-cell leukemia and HTLV-1-associated myelopathy. Adult T-cell leukemia development is mainly due to the ability of the viral oncoprotein Tax to promote T-cell proliferation, whereas the appearance of HTLV-1-associated myelopathy involves the antigenic properties of Tax. Understanding the events regulating the intracellular level of Tax is therefore an important issue. How Tax is degraded has not been determined, but it is known that Tax binds to proteasomes, the major sites for degradation of intracellular proteins, generally tagged through polyubiquitin conjugation. In this study, we investigated the relationship between Tax, ubiquitin, and proteasomes. We report that mono- and polyubiquitinated Tax proteins can be recovered from both transfected 293T cells and T lymphocytes. We also show that lysine residues located in the carboxy-terminal domain of Tax are the principal targets of this process. Remarkably, we further demonstrate that mutation of lysine residues in the C-terminal part of Tax, which massively reduces Tax ubiquitination, impairs proteasome binding, and conversely, that a Tax mutant that binds poorly to this particle (M22) is faintly ubiquitinated, suggesting that Tax ubiquitination is required for association with cellular proteasomes. Finally, we document that comparable amounts of ubiquitinated species were found whether proteasome activities were inhibited or not, providing evidence that they are not directly addressed to proteasomes for degradation. These findings indicate that although it is ubiquitinated and binds to proteasomes, Tax is not massively degraded via the ubiquitin-proteasome pathway and therefore reveal that Tax conjugation to ubiquitin mediates a nonproteolytic function.
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Lefèbvre, Laurent, Vincenzo Ciminale, Alain Vanderplasschen, Donna D'Agostino, Arsène Burny, Luc Willems, and Richard Kettmann. "Subcellular Localization of the Bovine Leukemia Virus R3 and G4 Accessory Proteins." Journal of Virology 76, no. 15 (August 1, 2002): 7843–54. http://dx.doi.org/10.1128/jvi.76.15.7843-7854.2002.
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ABSTRACT Bovine leukemia virus (BLV) is a complex retrovirus that belongs to the Deltaretrovirus genus, which also includes Human T-cell leukemia virus type 1 (HTLV-1). Both viruses contain an X region coding for at least four proteins: Tax and Rex, which are involved in transcriptional and posttranscriptional regulation, respectively, and the accessory proteins R3 and G4 (for BLV) and p12I, p13II, and p30II (for HTLV-1). The present study was aimed at characterizing the subcellular localization of BLV R3 and G4. The results of immunofluorescence experiments on transfected HeLa Tat cells demonstrated that R3 is located in the nucleus and in cellular membranes, as previously reported for HTLV-1 p12I. In contrast, G4, like p13II, is localized both in the nucleus and in mitochondria. In addition, we have shown that G4 harbors a mitochondrial targeting signal consisting of a hydrophobic region and an amphipathic α-helix. Thus, despite a lack of significant primary sequence homology, R3 and p12I and G4 and p13II exhibit similar targeting properties, suggesting possible overlap in their functional properties.
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Laverdure, Sylvain, Nicholas Polakowski, Kimson Hoang, and Isabelle Lemasson. "Permissive Sense and Antisense Transcription from the 5′ and 3′ Long Terminal Repeats of Human T-Cell Leukemia Virus Type 1." Journal of Virology 90, no. 7 (January 20, 2016): 3600–3610. http://dx.doi.org/10.1128/jvi.02634-15.
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ABSTRACTHuman T-cell leukemia virus type 1 (HTLV-1) is a retrovirus, and, as such, its genome becomes chromosomally integrated following infection. The resulting provirus contains identical 5′ and 3′ peripheral long terminal repeats (LTRs) containing bidirectional promoters. Antisense transcription from the 3′ LTR regulates expression of a single gene,hbz, while sense transcription from the 5′ LTR controls expression of all other viral genes, includingtax. Both the HBZ and Tax proteins are implicated in the development of adult T-cell leukemia (ATL), a T-cell malignancy caused by HTLV-1 infection. However, these proteins appear to harbor opposing molecular functions, indicating that they may act independently and at different time points prior to leukemogenesis. Here, we used bidirectional reporter constructs to test whether transcriptional interference serves as a mechanism that inhibits simultaneous expression of Tax and HBZ. We found that sense transcription did not interfere with antisense transcription from the 3′ LTR and vice versa, even with strong transcription emanating from the opposing direction. Therefore, bidirectional transcription across the provirus might not restricthbzortaxexpression. Single-cell analyses revealed that antisense transcription predominates in the absence of Tax, which transactivates viral sense transcription. Interestingly, a population of Tax-expressing cells exhibited antisense but not activated sense transcription. Consistent with the ability of Tax to induce cell cycle arrest, this population was arrested in G0/G1phase. These results imply that cell cycle arrest inhibits Tax-mediated activation of sense transcription without affecting antisense transcription, which may be important for long-term viral latency.IMPORTANCEThe chromosomally integrated form of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) contains identical DNA sequences, known as long terminal repeats (LTRs), at its 5′ and 3′ ends. The LTRs modulate transcription in both forward (sense) and reverse (antisense) directions. We found that sense transcription from the 5′ LTR does not interfere with antisense transcription from the 3′ LTR, allowing viral genes encoded on opposite DNA strands to be simultaneously transcribed. Two such genes aretaxandhbz, and while they are thought to function at different times during the course of infection to promote leukemogenesis of infected T cells, our results indicate that they can be simultaneously transcribed. We also found that the ability of Tax to induce cell cycle arrest inhibits its fundamental function of activating viral sense transcription but does not affect antisense transcription. This regulatory mechanism may be important for long-term HTLV-1 infection.
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Doucas, V., and R. M. Evans. "Human T-cell leukemia retrovirus-Tax protein is a repressor of nuclear receptor signaling." Proceedings of the National Academy of Sciences 96, no. 6 (March 16, 1999): 2633–38. http://dx.doi.org/10.1073/pnas.96.6.2633.
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Bazarbachi, Ali, Hiba El Hajj, Marwan El-Sabban, Hideki Hasegawa, Ghazi Zaatari, Shahrazad Saab, Anne Janin, et al. "The Combination of Arsenic Trioxide and Interferon-Alpha Eradicates Leukemia Initiating Cells in TAX-Driven Murine Adult T Cell Leukemia/Lymphoma." Blood 114, no. 22 (November 20, 2009): 2714. http://dx.doi.org/10.1182/blood.v114.22.2714.2714.
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Abstract Abstract 2714 Poster Board II-690 Adult T cell leukemia (ATL) is one of the rare human cancers initiated by a transforming retrovirus, HTLV-I. After many years of controversy, it is now accepted that the viral transactivator protein Tax plays a critical role in initiating the leukemic process, because Tax transgenics develop a disease with striking ATL features. Long-term prognosis of ATL patients remains extremely poor, but we recently reported that the combination of As2O3, interferon-a (IFN), and zidovudine yielded unprecedented response rates. Indeed, in 10 chronic ATL patients, a 100% response rate was observed, including 7 complete remissions (CR), 2 CR but with more than 5% circulating atypical lymphocytes, and one partial response. We demonstrate that the As2O3/IFN combination, previously shown to degrade Tax, cures Tax-driven murine ATLs. Unexpectedly, this combination immediately abrogates leukemia transplantation into secondary recipients, while the primary tumor continues to grow and only exhausts much later. Leukemia initiating cell (LIC) clearance is reversed by proteasome inhibition, demonstrating that LICs are addicted to continuous Tax expression. Most anticancer treatments fail to target LIC. These results establish that As2O3/IFN/zidovudine acts through Tax targeting and predict a favorable long-term outcome for responsive patients. Thus, oncogene degradation can selectively target LICs, explaining this very recent success of a similar regimen in patients. Disclosures: No relevant conflicts of interest to declare.
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Brady, H. J., C. G. Miles, D. J. Pennington, and E. A. Dzierzak. "Specific ablation of human immunodeficiency virus Tat-expressing cells by conditionally toxic retroviruses." Proceedings of the National Academy of Sciences 91, no. 1 (January 4, 1994): 365–69. http://dx.doi.org/10.1073/pnas.91.1.365.
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Tajima, Shigeru, and Yoko Aida. "The Region between Amino Acids 245 and 265 of the Bovine Leukemia Virus (BLV) Tax Protein Restricts Transactivation Not Only via the BLV Enhancer but Also via Other Retrovirus Enhancers." Journal of Virology 74, no. 23 (December 1, 2000): 10939–49. http://dx.doi.org/10.1128/jvi.74.23.10939-10949.2000.
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ABSTRACT Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis and is closely related to human T-cell leukemia virus type 1 (HTLV-1). The Tax protein of BLV acts through the 5′ long terminal repeat (LTR) of BLV and activates the transcription of BLV. In this study, we amplified tax genes from BLV-infected cattle using PCR. We cloned the genes and monitored the transcriptional activities of the products. Seven independent mutant Tax proteins, with at least one amino acid substitution between residues 240 and 265, exhibited a markedly stronger ability to stimulate the viral LTR-directed transcription than the wild-type Tax protein. Analysis of chimeric Tax proteins derived from wild-type and mutant Tax proteins clearly demonstrated that a single substitution between residue 240 and 265 might be critical for the higher activities of the Tax mutant proteins. Furthermore, it appeared that transient expression of a Tax mutant protein was better able to increase the production of viral proteins and particles from a defective recombinant proviral clone of BLV than was wild-type Tax. Analysis of mutations within the U3 region of the LTR revealed that a cyclic AMP-responsive element in Tax-responsive element 2 might be sufficient for the enhanced activation mediated by the mutant proteins. In addition to the LTR of BLV, other viral enhancers, such as the enhancers of HTLV-1 and of mouse mammary tumor virus, which cannot be activated by wild-type BLV Tax protein, were activated by a Tax mutant protein. Our observations suggest that the transactivation activity and target sequence specificity of BLV Tax might be limited or negatively regulated by the region of the protein between amino acids 240 and 265.
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Ishikawa, Chie, Taeko Okudaira, Tetsuro Nakazato, Mariko Tomita, and Naoki Mori. "Human T-Cell Leukemia Virus Type I Tax Activates CD69 Gene Expression." Blood 108, no. 11 (November 1, 2006): 2256. http://dx.doi.org/10.1182/blood.v108.11.2256.2256.
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Abstract The human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is etiologically linked to the genesis of adult T-cell leukemia (ATL). Emerging evidence suggests that the pathogenicity of ATL involves suppression of the overall immune response, although the underlying mechanism remains unclear. In this study, we demonstrated that HTLV-I transactivator Tax induces the aberrant expression of CD69, an early leukocyte activation molecule that plays an important role in downregulation of the immune response. In a panel of HTLV-I-infected T-cell lines, CD69 expression was highly elevated compared to HTLV-I-negative T-cell lines at both mRNA and protein levels. Furthermore, CD69 expression correlated with Tax expression. Peripheral blood mononuclear cells from ATL patients also showed an increased expression of CD69 compared with controls. In vitro infection of a T-cell line with HTLV-I was associated with CD69 expression in conjunction with the increasing Tax expression. Expression of CD69 was dependent upon Tax expression in the inducible Tax-expressing cell line JPX-9. Tax transactivated the CD69 gene promoter in a transient transfection assay. Using Tax mutants and dominant negative mutants of IκBs, IKKs, NIK, and CREB, we demonstrated that Tax-induced CD69 expression required the NF-κB and CREB signaling pathways. A series of deletion and mutation analyses of the CD69 gene promoter indicated that two NF-κB, two EGR, and a CRE sequences were critical for Tax transactivation. Electrophoretic mobility shift assay showed the formation of specific protein-DNA complexes in HTLV-I-infected T-cell lines. These results suggest that Tax directly transactivated CD69 gene expression, through multiple cis-acting elements and by the interplay of transcription factors of the NF-κB, EGR, and CREB families. Tax-induced CD69 expression may be involved in immune suppression in ATL.
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Younis, Ihab, Brenda Yamamoto, Andrew Phipps, and Patrick L. Green. "Human T-Cell Leukemia Virus Type 1 Expressing Nonoverlapping Tax and Rex Genes Replicates and Immortalizes Primary Human T Lymphocytes but Fails To Replicate and Persist In Vivo." Journal of Virology 79, no. 23 (December 15, 2005): 14473–81. http://dx.doi.org/10.1128/jvi.79.23.14473-14481.2005.
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ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus associated primarily with adult T-cell leukemia and neurological disease. HTLV-1 encodes the positive trans-regulatory proteins Tax and Rex, both of which are essential for viral replication. Tax activates transcription initiation from the viral long terminal repeat and modulates the transcription or activity of a number of cellular genes. Rex regulates gene expression posttranscriptionally by facilitating the cytoplasmic expression of incompletely spliced viral mRNAs. Tax and Rex mutants have been identified that have defective activities or impaired biochemical properties associated with their function. To ultimately determine the contribution of specific protein activities on viral replication and cellular transformation of primary T cells, mutants need to be characterized in the context of an infectious molecular clone. Since the tax and rex genes are in partially overlapping reading frames, mutation in one gene frequently disrupts the other, confounding interpretation of mutational analyses in the context of the virus. Here we generated and characterized a unique proviral clone (H1IT) in which the tax and rex genes were separated by expressing Tax from an internal ribosome entry site. We showed that H1IT expresses both functional Tax and Rex. In short- and long-term coculture assays, H1IT was competent to infect and immortalize primary human T cells similar to wild-type HTLV-1. In contrast, H1IT failed to efficiently replicate and persist in inoculated rabbits, thus emphasizing the importance of temporal and quantitative regulation of specific mRNA for viral survival in vivo.
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Ma, Guangyong, Jun-ichirou Yasunaga, Hirofumi Akari, and Masao Matsuoka. "TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): 2216–21. http://dx.doi.org/10.1073/pnas.1419198112.
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Human T-cell leukemia virus type 1 (HTLV-1) is a delta-type retrovirus that induces malignant and inflammatory diseases during its long persistence in vivo. HTLV-1 can infect various kinds of cells; however, HTLV-1 provirus is predominantly found in peripheral CD4 T cells in vivo. Here we find that TCF1 and LEF1, two Wnt transcription factors that are specifically expressed in T cells, inhibit viral replication through antagonizing Tax functions. TCF1 and LEF1 can each interact with Tax and inhibit Tax-dependent viral expression and activation of NF-κB and AP-1. As a result, HTLV-1 replication is suppressed in the presence of either TCF1 or LEF1. On the other hand, T-cell activation suppresses the expression of both TCF1 and LEF1, and this suppression enables Tax to function as an activator. We analyzed the thymus of a simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaque, and found a negative correlation between proviral load and TCF1/LEF1 expression in various T-cell subsets, supporting the idea that TCF1 and LEF1 negatively regulate HTLV-1 replication and the proliferation of infected cells. Thus, this study identified TCF1 and LEF1 as Tax antagonistic factors in vivo, a fact which may critically influence the peripheral T-cell tropism of this virus.
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Schnell, Annika P., Stephan Kohrt, and Andrea K. Thoma-Kress. "Latency Reversing Agents: Kick and Kill of HTLV-1?" International Journal of Molecular Sciences 22, no. 11 (May 24, 2021): 5545. http://dx.doi.org/10.3390/ijms22115545.
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Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.
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Fujita, M., K. Murata, and H. Shiku. "Selective inhibition of human T-lymphotropic virus type I-transformed human T-cell growth by a tax-targeted conditionally cytotoxic recombinant retrovirus." Blood 84, no. 8 (October 15, 1994): 2591–96. http://dx.doi.org/10.1182/blood.v84.8.2591.2591.
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Abstract Adult T-cell leukemia (ATL), a disorder associated with high mortality rates, arises from human T-lymphotropic virus type I (HTLV-I)-infected CD4+ T cells. We designed a retroviral vector-based gene therapy approach to ATL. The long terminal repeat (LTR) of HTLV-I is transactivated by the viral tax protein. We constructed a hybrid gene consisting of herpes simplex virus thymidine kinase (HSV TK) under the control of the HTLV-I LTR and inserted it into a retroviral vector. When HTLV-I-transformed and tax-expressing human T-cell lines were infected with this recombinant retrovirus (LNLTK alpha virus), they expressed high levels of HSV TK and exhibited increased sensitivity to acyclovir, a nucleoside analog that is converted to the toxic anabolite after phosphorylation by the HSV TK. On the other hand, the retroviral infection had little effect on acyclovir-induced cytotoxicity in HTLV-I- negative human hematopoietic cell lines. Our data may provide the prospect of the gene therapy for ATL by tax-targeted selective elimination of leukemic cells.
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Fujita, M., K. Murata, and H. Shiku. "Selective inhibition of human T-lymphotropic virus type I-transformed human T-cell growth by a tax-targeted conditionally cytotoxic recombinant retrovirus." Blood 84, no. 8 (October 15, 1994): 2591–96. http://dx.doi.org/10.1182/blood.v84.8.2591.bloodjournal8482591.
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Adult T-cell leukemia (ATL), a disorder associated with high mortality rates, arises from human T-lymphotropic virus type I (HTLV-I)-infected CD4+ T cells. We designed a retroviral vector-based gene therapy approach to ATL. The long terminal repeat (LTR) of HTLV-I is transactivated by the viral tax protein. We constructed a hybrid gene consisting of herpes simplex virus thymidine kinase (HSV TK) under the control of the HTLV-I LTR and inserted it into a retroviral vector. When HTLV-I-transformed and tax-expressing human T-cell lines were infected with this recombinant retrovirus (LNLTK alpha virus), they expressed high levels of HSV TK and exhibited increased sensitivity to acyclovir, a nucleoside analog that is converted to the toxic anabolite after phosphorylation by the HSV TK. On the other hand, the retroviral infection had little effect on acyclovir-induced cytotoxicity in HTLV-I- negative human hematopoietic cell lines. Our data may provide the prospect of the gene therapy for ATL by tax-targeted selective elimination of leukemic cells.
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Béraud, C., S. C. Sun, P. Ganchi, D. W. Ballard, and W. C. Greene. "Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency." Molecular and Cellular Biology 14, no. 2 (February 1994): 1374–82. http://dx.doi.org/10.1128/mcb.14.2.1374.
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Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67SRF. An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-1 latency observed in adult T-cell leukemia.
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Béraud, C., S. C. Sun, P. Ganchi, D. W. Ballard, and W. C. Greene. "Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency." Molecular and Cellular Biology 14, no. 2 (February 1994): 1374–82. http://dx.doi.org/10.1128/mcb.14.2.1374-1382.1994.
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Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of the adult T-cell leukemia, an aggressive and often fatal malignancy of activated human CD4 T cells. HTLV-I encodes an essential 40-kDa protein termed Tax that not only transactivates the long terminal repeat of this retrovirus but also induces an array of cellular genes. Tax-mediated transformation of T cells likely involves the deregulated expression of various cellular genes that normally regulate lymphocyte growth produced by altered activity of various endogenous host transcription factors. In particular, Tax is capable of modulating the expression or activity of various host transcription factors, including members of the NF-kappa B/Rel and CREB/ATF families, as well as the cellular factors HEB-1 and p67SRF. An additional distinguishing characteristic of HTLV-I infection is the profound state of viral latency that is present in circulating primary leukemic T cells. In this study, we demonstrate that HTLV-I Tax can physically associate with p100, the product of the Rel-related NF-kappa B2 gene, both in transfected cells and in HTLV-I-infected leukemic T-cell lines. Furthermore, the physical interaction of Tax with p100 leads to the inhibition of Tax-induced activation of the HTLV-I and human immunodeficiency virus type 1 long terminal repeats, reflecting p100-mediated cytoplasmic sequestration of the normally nuclearly expressed Tax protein. In contrast, a mutant of Tax that selectively fails to activate nuclear NF-kappa B expression does not associate with p100. Together, these results suggest that the cytoplasmic interplay of Tax and p100 may play an important role in the initiation and maintenance of HTLV-1 latency observed in adult T-cell leukemia.
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Nitta, Takayuki, Andrew Hofacre, Stacey Hull, and Hung Fan. "Identification and Mutational Analysis of a Rej Response Element in Jaagsiekte Sheep Retrovirus RNA." Journal of Virology 83, no. 23 (September 23, 2009): 12499–511. http://dx.doi.org/10.1128/jvi.01754-08.
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ABSTRACT Jaagsiekte sheep retrovirus (JSRV) is a simple betaretrovirus causing a contagious lung cancer of sheep. JSRV encodes unspliced and spliced viral RNAs, among which unspliced RNA encodes Gag and Pol proteins and a singly spliced mRNA encodes Env protein. In another study we found that JSRV encodes a regulatory protein, Rej, that is responsible for synthesis of Gag polyprotein from unspliced viral RNA. Rej is encoded in the 5′ end of env, and it enhances nuclear export or accumulation of cytoplasmic unspliced viral RNA in 293T cells but not in most other cell lines (A. Hofacre, T. Nitta, and H. Fan, J. Virol. 83:12483-12498, 2009). In this study, we found that mutations in the 3′ end of env in the context of a cytomegalovirus-driven full-length JSRV expression construct abolished Gag protein synthesis and released viruses in 293T cells. These mutants also showed deficits in accumulation of unspliced viral RNA in the cytoplasm. These mutants defined a Rej-responsive element (RejRE). Inhibition of CRM1 but not Tap function prevented nuclear export/accumulation of cytoplasmic unspliced RNA in 293T cells, similarly to other complex retroviruses that express analogous regulator proteins (e.g., human immunodeficiency virus Rev). Structural modeling of the RejRE with Zuker M-fold indicated a region with a predicted stable secondary structure. Mutational analysis in this region indicated the importance of both secondary structures and primary nucleotide sequences in a central stem-bulge-stem structure. In contrast to 293T cells, mutations in the RejRE did not affect the levels of cytoplasmic unspliced RNA in 293 cells, although the unspliced RNA showed partial degradation, perhaps due to lack of translation. RejRE-containing RNA relocalized Rej protein from the nucleus to the cytoplasm in 293 and rat 208F cells, suggesting binding of Rej to the RejRE.
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Geleziunas, Romas, Sharon Ferrell, Xin Lin, Yajun Mu, Emmett T. Cunningham, Mark Grant, Margery A. Connelly, John E. Hambor, Kenneth B. Marcu, and Warner C. Greene. "Human T-Cell Leukemia Virus Type 1 Tax Induction of NF-κB Involves Activation of the IκB Kinase α (IKKα) and IKKβ Cellular Kinases." Molecular and Cellular Biology 18, no. 9 (September 1, 1998): 5157–65. http://dx.doi.org/10.1128/mcb.18.9.5157.
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ABSTRACT Tax corresponds to a 40-kDa transforming protein from the pathogenic retrovirus human T-cell leukemia virus type 1 (HTLV-1) that activates nuclear expression of the NF-κB/Rel family of transcription factors by an unknown mechanism. Tax expression promotes N-terminal phosphorylation and degradation of IκBα, a principal cytoplasmic inhibitor of NF-κB. Our studies now demonstrate that HTLV-1 Tax activates the recently identified cellular kinases IκB kinase α (IKKα) and IKKβ, which normally phosphorylate IκBα on both of its N-terminal regulatory serines in response to tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) stimulation. In contrast, a mutant of Tax termed M22, which does not induce NF-κB, fails to activate either IKKα or IKKβ. Furthermore, endogenous IKK enzymatic activity was significantly elevated in HTLV-1-infected and Tax-expressing T-cell lines. Transfection of kinase-deficient mutants of IKKα and IKKβ into either human Jurkat T or 293 cells also inhibits NF-κB-dependent reporter gene expression induced by Tax. Similarly, a kinase-deficient mutant of NIK (NF-κB-inducing kinase), which represents an upstream kinase in the TNF-α and IL-1 signaling pathways leading to IKKα and IKKβ activation, blocks Tax induction of NF-κB. However, plasma membrane-proximal elements in these proinflammatory cytokine pathways are apparently not involved since dominant negative mutants of the TRAF2 and TRAF6 adaptors, which effectively block signaling through the cytoplasmic tails of the TNF-α and IL-1 receptors, respectively, do not inhibit Tax induction of NF-κB. Together, these studies demonstrate that HTLV-1 Tax exploits a distal part of the proinflammatory cytokine signaling cascade leading to induction of NF-κB. The pathological alteration of this cytokine pathway leading to NF-κB activation by Tax may play a central role in HTLV-1-mediated transformation of human T cells, clinically manifested as the adult T-cell leukemia.
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Hyun, Jinhee, Juan Carlos Ramos, Ngoc Toomey, Siddharth Balachandran, Alfonso Lavorgna, Edward Harhaj, and Glen N. Barber. "Oncogenic Human T-Cell Lymphotropic Virus Type 1 Tax Suppression of Primary Innate Immune Signaling Pathways." Journal of Virology 89, no. 9 (February 18, 2015): 4880–93. http://dx.doi.org/10.1128/jvi.02493-14.
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ABSTRACTHuman T-cell lymphotropic virus type I (HTLV-1) is an oncogenic retrovirus considered to be the etiological agent of adult T-cell leukemia (ATL). The viral transactivator Tax is regarded as the oncoprotein responsible for contributing toward the transformation process. Here, we demonstrate that Tax potently inhibits the activity of DEx(D/H) box helicases RIG-I and MDA5 as well as Toll-dependent TIR-domain-containing adapter-inducing interferon-β (TRIF), which function as cellular sensors or mediators of viral RNA and facilitate innate immune responses, including the production of type I IFN. Tax manifested this function by binding to the RIP homotypic interaction motif (RHIM) domains of TRIF and RIP1 to disrupt interferon regulatory factor 7 (IRF7) activity, a critical type I IFN transcription factor. These data provide further mechanistic insight into HTLV-1-mediated subversion of cellular host defense responses, which may help explain HTLV-1-related pathogenesis and oncogenesis.IMPORTANCEIt is predicted that up to 15% of all human cancers may involve virus infection. For example, human T-cell lymphotropic virus type 1 (HTLV-1) has been reported to infect up to 25 million people worldwide and is the causative agent of adult T-cell leukemia (ATL). We show here that HTLV-1 may be able to successfully infect the T cells and remain latent due to the virally encoded product Tax inhibiting a key host defense pathway. Understanding the mechanisms by which Tax subverts the immune system may lead to the development of a therapeutic treatment for HTLV-1-mediated disease.
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Zhang, Weiqing, John W. Nisbet, Joshua T. Bartoe, Wei Ding, and Michael D. Lairmore. "Human T-Lymphotropic Virus Type 1 p30IIFunctions as a Transcription Factor and Differentially Modulates CREB-Responsive Promoters." Journal of Virology 74, no. 23 (December 1, 2000): 11270–77. http://dx.doi.org/10.1128/jvi.74.23.11270-11277.2000.
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ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1), a complex retrovirus, causes adult T-cell lymphoma/leukemia and is linked to a variety of immune-mediated disorders. The roles of proteins encoded in the pX open reading frame (ORF) II gene region in HTLV-1 replication or in mediating virus-associated diseases remain to be defined. A nucleus-localizing 30-kDa protein, p30II, encoded within pX ORF II has limited homology with the POU family of transcription factors. Recently, we reported that selected mutations in pX ORF II diminish the ability of HTLV-1 to maintain high viral loads in infected rabbits. Herein we have tested the transcriptional ability of p30II in mammalian cells by using yeast Gal4 fusion protein vectors and transfection of luciferase reporter genes driven by CREB-responsive promoters. p30II as a Gal4 DNA-binding domain (DBD) fusion protein transactivates Gal4-driven luciferase reporter gene activity up to 25-fold in 293 and HeLa-tat cells. We confirmed nuclear localization of p30II and demonstrate dose-dependent binding of p30II-Gal4(DBD) to Gal4 DNA-binding sites. The transcriptional activity of p30II-Gal4(DBD) was independent of TATA box flanking sequences, as shown by using two different Gal4 reporter systems. Studies of selected p30II mutants indicated that domains that mediate transcription are restricted to a central core region of the protein between amino acids 62 and 220. Transfection of a p30II-expressing plasmid repressed cellular CRE-driven reporter gene activity, with or without Tax expression. In contrast, p30II at lower concentrations enhanced HTLV-1 long terminal repeat-driven reporter gene activity independent of Tax expression. These data are the first to demonstrate a transcriptional function for p30II and suggest a mechanism by which this nuclear protein may influence HTLV-1 replication or cellular gene expression in vivo.
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Bodem, Jochen, Hans-Georg Kräusslich, and Axel Rethwilm. "Acetylation of the foamy virus transactivator Tas by PCAF augments promoter-binding affinity and virus transcription." Journal of General Virology 88, no. 1 (January 1, 2007): 259–63. http://dx.doi.org/10.1099/vir.0.82169-0.
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It was shown recently that retrovirus transactivators interact with transcriptional coactivators, such as histone acetyltransferases (HATs). Foamy viruses (FVs) direct gene expression from the long terminal repeat and from an internal promoter. The activity of both promoters is strictly dependent on the DNA-binding transactivator Tas. Recently, it was shown that Tas interacts with the HATs p300 and PCAF. Based on these findings, it is demonstrated here that PCAF has the ability to acetylate Tas in vitro and in vivo. Tas acetylation resulted in enhanced DNA binding to the virus promoters. In vitro transcription reactions on non-chromatinized template showed that only acetylated Tas enhanced transcription significantly. These results demonstrate that acetylation of the FV transactivator Tas may be an effective means to regulate virus transcription.
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Dolei, Antonina, Elena Uleri, Gabriele Ibba, Maurizio Caocci, Claudia Piu, and Caterina Serra. "The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration." Journal of Infection in Developing Countries 9, no. 06 (July 4, 2015): 577–87. http://dx.doi.org/10.3855/jidc.6916.
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The human genome contains remnants of ancestral retroviruses now endogenously transmitted, called human endogenous retroviruses (HERVs). HERVs can be variably expressed, and both beneficial and detrimental effects have described. This review focuses on the MSRV and syncytin-1 HERV-W elements in relationship to neurodegeneration in view of their neuro-pathogenic and immune-pathogenic properties. Multiple sclerosis (MS) and a neurodegenerative disease (neuroAIDS) are reported in this review. In vivo studies in patients and controls for molecular epidemiology and follow-up studies are reviewed, along with in vitro cellular studies of the effects of treatments and of molecular mechanisms. HERV-W/MSRV has been repeatedly found in MS patients (in blood, spinal fluid, and brain samples), and MRSV presence/load strikingly parallels MS stages and active/remission phases, as well as therapy outcome. The DNA of MS patients has increased MSRVenv copies, while syncytin-1 copies are unchanged in controls. Presence of MSRV in the spinal fluid predicted the worst MS progression, ten years in advance. The Epstein-Barr virus (EBV) activates HERV-W/MSRV both in vitro and in vivo. With respect to neuroAIDS, the HIV transactivator of transcription (Tat) protein activates HERV-W/MSRV in monocytes/macrophages and astrocytes indirectly by interaction with TLR4 and induction of TNFa. HERV-W/MSRV can be considered a biomarker for MS behavior and therapy outcome. Regarding MS pathogenesis, we postulate the possibility for EBV of an initial trigger of future MS, years later, and for MSRV of a direct role of effector of neuropathogenesis during MS. Additionally, HERV-W/MSR/syncytin-1 activation by HIV Tat could contribute to the HIV-related neurodegeneration.