The trans-activator protein Tax of human T-cell leukemia virus type 1 (HTLV-1) activates the viral 21-base-pair (bp) enhancer in the long terminal repeat and has been suggested to associate indirectly with the enhancer DNA. To demonstrate this, we used DNA-affinity precipitation assay and detected the Tax protein in 21-bp DNA-protein complexes isolated from HTLV-1-infected cells. To identify cellular components in the complexes, we tested various 21-bp DNAbinding proteins by gel electrophoretic mobility-shift assay. Furthermore, the Tax-CREB complex was detected in a nuclear extract of HTLV-1-infected cells, and the Tax-CREB-21-bp-DNA complex was demonstrated as a major component of Tax complexes containing the 21-bp DNA probe. These observations indicate that Tax protein binds to CREB and CRE modulator and the complexes then bind to the 21-bp enhancer, suggesting that the complex binding to the enhancer mediates trans-activation of transcription.
To estimate the replication of the human T-cell leukemia virus type I (HTLV-I) in patients with HTLV-I-associated myelopathy (HAM), or tropical spastic paraparesis (TSP), HTLV-I DNA integrated into lymphocyte genomes was analyzed by Southern blot hybridization. HTLV-I DNA was detected in 125 (82%) of 153 patients and most showed random integration. This incidence was much higher than the 29% found in asymptomatic carriers. Therefore, HAM/TSP development is associated with a high level of HTLV-I replication. In addition, lymphocytes from 3 patients with HAM/TSP showed monoclonal integration of HTLV-I DNA, indicating adult T-cell leukemia.
The trans activator (p4Oax) of human T-cell leukemia virus type I (HTLV-I) is a transcriptional factor that activates the long terminal repeat (LTR) of HTLV-I and interleukin-2 receptor ca. We examined the HTLV-I enhancer responsible for tax-mediated trans activation and identified (A/T)(G/C)(G/C)CNNTGACG(T/A) as a plausible tax-responsive element (TRE). The putative TRE in the LTR was found to be different from the elements required for activation by cyclic AMP and 12-0-tetradecanoylphorbol-13-acetate, although these elements overlapped each other. The TRE was also different from a binding site of an NF-KB-like factor that was identified in the interleukin-2 receptor a promoter and human immunodeficiency virus LTR as a TRE. The latter result was further demonstrated by the failure of the NF-KB sequence to compete with the TRE of the LTR in a protein-binding assay. These findings indicate that tax function and its cascade can modulate activities of various enhancer sequences, which are probably regulated by distinct DNA-binding factors.
trans-activator p40 of human T-cell leukemia virus type I activates specific enhancers and stimulates transcription of the viral and some cellular genes but does not bind directly to the enhancer sequences. We demonstrated here that a fusion protein of p4Ot^l and GAL4 DNA binding domain activated transcription dependent on the GAL4-binding site in the reporter plasmid. Mutants of p40 were also tested in the fusion protein, and their activities were found to be in parallel with those of their free forms on the original target long terminal repeat. This activation with GAL4 fusion protein was interfered with by the free form of p4Ot. These results suggest that p4Ofax associates with DNA through interaction with DNA binding protein(s) and also interacts with another transcription factor(s) to elicit the activation. Human T-cell leukemia virus type I (HTLV-I) is an etiologic agent of adult T-cell leukemia (25, 37). Replication of HTLV-I is regulated at transcriptional (2, 6, 28, 32) and posttranscriptional (9, 11, 12) levels by its own products, TAX and REX, respectively. The tax gene product, p4fax,
Human T-cell leukemia virus type 1 (HTLV-1) integrates its proviruses into random sites in host chromosomal DNA. Random integration of the proviruses was observed in asymptomatic HTLV-1 carriers and patients with HTLV-1-associated myelopathy (HAM/TSP). However, clonal integration has been reported in patients with adult T-cell leukemia (ATL), including that in the smoldering, chronic, and acute states, indicating clonal expansion of infected cells. In this study, we found that about 20% of HAM/TSP patients and their seropositive family members harbored subpopulation(s) of clonally proliferated cells infected with HTLV-1, although they still maintained randomly infected cells as a major population. These clones were stable during examination periods of 4 months to 3 years. However, these carriers or HAM/TSP patients did not show any significant indication of ATL. This extremely high frequency of clonal expansion of HTLV-1-infected cells indicates that some clones of HTLV-1-infected cells have a tendency to proliferate more efficiently than the other population without malignant transformation.
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