Upregulation of Human T-Cell Leukemia Virus Type 1 Antisense Transcription by the Viral Tax Protein

Abstract

Several studies have recently demonstrated the existence of human T-cell leukemia virus type 1 (HTLV-1) antisense transcripts, which allow the synthesis of the newly described HBZ protein. Although previous reports have been aimed at understanding the potential role of the HBZ protein in HTLV-1 pathogenesis, little is known as to how this viral gene is regulated. Here, using our K30-3asLuc reporter construct, we show that the viral Tax protein upregulates antisense transcription through its action on the TRE sequences located in the 3 long terminal repeat. Generation of stable clones in 293T cells demonstrated that Tax-induced HBZ expression is importantly influenced by the integration site in the host genome. The cellular DNA context could thus affect the level of HBZ mRNA expression in infected cells.Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (13,29,34,35,37,46), leading to disease development in less than 5% of infected individuals (42). The HTLV-1 Tax protein is generally considered to play a central role in the viral pathogenesis, although its precise function remains to be determined. Tax transactivates the viral promoter, mainly through three Tax responsive element 1 (TRE1) repeats located in the U3 region of the 5Ј long terminal repeat (LTR) (14,15,17,19,44). Each TRE1 repeat contains an imperfect cyclic AMP response element (CRE), and they are crucial for both basal and Tax-induced promoter activity (14,15,17,19,44). Tax associates with TRE1-bound ATF/CREB transcription factors and recruits the transcriptional coactivator CBP/p300, which results in a strong transcriptional activation (12,22). Tax also upregulates the expression of cellular genes through the activation of several transcription factors, such as CREB-1, NF-B and SRF (1,30,45).Recently, we (6) and others (31, 39) have clearly demonstrated the existence of antisense transcripts in HTLV-1, which initiate from the 3Ј LTR. These transcripts are alternatively spliced and encode the newly described HTLV-1 bZIP factor (HBZ) through an ATG initiation codon being present in exon 1 located in the 3Ј LTR. Interestingly, HBZ downregulates the Tax-dependent transactivation of viral gene expression through the formation of heterodimers with CREB-1 and CREB-2. In addition, HBZ interacts with c-Jun, JunB, and JunD and modulates their transcriptional activities (4, 24, 41).Recent studies have shown that HBZ is expressed in all ATL cell lines, suggesting that it might play an unsuspected role in the biological process leading to ATLL development (28,43).Despite the increasing number of studies aimed at understanding the role of HBZ in viral pathogenesis, little is known about the promoter region regulating its expression. In order to clarify this issue, we have performed several transfection experiments using our previously described K30-3ЈasLuc construct (6). In this construct, a cassette containing the luciferase r...

Permissive Sense and Antisense Transcription from the 5′ and 3′ Long Terminal Repeats of Human T-Cell Leukemia Virus Type 1

“…Contrasting results have been obtained regarding the role of Tax in the regulation of HTLV-1 antisense transcription. Specifically, Tax has not been shown to affect antisense transcription from an HTLV-1 LTR lacking additional proviral sequence (2, 6); however, it has been found to activate antisense transcription from a proviral construct with a 5= deletion (41). These observations suggest that the ability of Tax to augment antisense transcription involves a region of DNA located outside the 3= LTR.…”

Analysis of Blood Transcriptome in Patients With Chronic Kidney Disease of Uncertain Aetiology

“…The 7SK small nuclear RNA (RN7SK) functions as a negative regulator of HIV-1 transcription by interacting with the positive elongation factor b (p-TEFb) [17] . The upregulation of the Human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor gene (HBZ) has been associated with HTLV-1, the cause of Adult T-cell leukemia/lymphoma (ATL) [18,19]. The HBZ gene was also suggested to possibly have a functional role in cellular transformation and leukemogenesis [19].…”

Human T-Cell Lymphotropic Virus Type 3 (HTLV-3)- and HTLV-4-Derived Antisense Transcripts Encode Proteins with Similar Tax-Inhibiting Functions but Distinct Subcellular Localization

“…Similar results have been obtained with the HBZ promoter (12). It might be expected that, as for HBZ expression, Tax expression would induce their expression via equivalent Tax-responsive element (TRE) sequences within the U3 region of the LTR (28,52). Current experiments are addressing this possibility.…”