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PubMed2006

Reduced Foxp3 protein expression is associated with inflammatory disease during human t lymphotropic virus type 1 Infection.

The Foxp3 protein is a specific marker of CD4(+)CD25(+) regulatory T (T(reg)) cells, and its expression is critical to their development and function. Several studies have demonstrated the dysregulation of Foxp3 expression during human inflammatory diseases. Infection with human T lymphotropic virus type 1 (HTLV-1) is associated with the development of a number of inflammatory conditions, including myelopathy, although the majority of individuals who are infected with HTLV-1 remain asymptomatic. To examine the role played by T(reg) cells in the development of inflammatory disease during HTLV-1 infection, we examined Foxp3 expression by flow cytometry. Our analysis showed that HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with a lower expression (compared with that in asymptomatic HTLV-1 carriers and healthy donors) of Foxp3 in peripheral-blood leukocytes. In individuals infected with HTLV-1, Foxp3 expression was inversely correlated with HTLV-1 tax proviral DNA load. These results suggest that impaired Foxp3 expression may contribute to the development of inflammatory disease during HTLV-1 infection.

CD4 Antigens↗
PubMed2000

HTLV type I/II in British Columbia Amerindians: a seroprevalence study and sequence characterization of an HTLV type IIa isolate.

It has been established that the human T cell lymphotropic viruses type I and II (HTLV-I and HTLV-II) are both present in some indigenous peoples of the Americas. While HTLV-I has been identified in coastal British Columbia Indians (BCIs), HTLV-II has not been previously reported in the BCIs or other Canadian Amerindians. The prevalence of HTLV-I and HTLV-II in these populations has not been extensively studied. In this article, we examine a group of BCIs from Vancouver Island who belong to the Nuu-Chah-Nulth and are known to have an increased incidence of rheumatic disease. In 494 serum samples from this tribe, the levels of prevalence of HTLV-I and HTLV-II were 2.8 and 1.6%, respectively. No association could be made between arthropathy and HTLV-I infection. In addition, we characterized an HTLV-II isolate of a BCI from the coastal mainland of British Columbia and with a history of intravenous drug abuse. This case represents the first molecular characterization of a Canadian Amerindian HTLV-II isolate: a subtype IIa virus with phylogenetic affinity for intravenous drug user isolates and containing an extended form of the Tax protein. These results are consistent either with this strain having been sampled from a polymorphic ancestral pool of HTLV-II that gave rise to the current epidemic spread of this virus by intravenous drug use and sexual transmission, or with its being "back-transmitted" into the BC Amerindian population in association with intravenous drug use.

Base Sequence↗
PubMed2001

Cell-type-specific trans-activation of herpes simplex virus thymidine kinase promoter by the human T-cell leukemia virus type I Tax protein.

The human T-cell leukemia virus type I Tax protein (HTLV-I Tax) is known as a trans-activating factor for a variety of genes, including those of cytokines. Here, we show that Tax is capable of activating the herpes simplex virus thymidine kinase (HSV-TK) promoter in certain mammalian cell lines. In murine NIH 3T3 fibroblasts and human HeLa cells, trans-activation by Tax was remarkably strong, whereas in human chondrocytic HCS-2/8 and monkey kidney Cos-7 cells, the responsiveness of the TK promoter to Tax was poor. Deletion analysis revealed that one of the two previously described Sp1 sites is required for the Tax responsiveness, whereas the CTF binding site is not. The results suggest possible interactions between the oncogenic Tax protein and the viral TK in coinfected cells in vivo. Care should be taken in the context of HTLV-I research, as the HSV-TK promoter has been widely used in molecular biology and gene therapeutics.

3T3 Cells↗
PubMed2003

Novel enzyme-linked immunosorbent assay systems for the quantitative analysis of connective tissue growth factor (CTGF/Hcs24/CCN2): detection of HTLV-I tax-induced CTGF from a human carcinoma cell line.

Connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24/CCN2) is known as a multifunctional growth factor. It stimulates proliferation, migration, and extracellular matrix production of mesenchymal cells, and is highly expressed in hypertrophic chondrocytes. In this study, we constructed useful ELISA systems for the analysis of CTGF and its modular fragments. For this objective we prepared four different antihuman CTGF monoclonal antibodies. One, specific for the VWC module, was utilized as the detecting antibody, and the other three, recognizing CT, IGFBP, and VWC modules, respectively, were employed as capture antibodies. Then we established three novel quantitative analysis systems for CTGF. The first system recognizing CT and VWC modules was useful to measure full-length CTGF with improved sensitivity. Utilizing this system, we found significant enhancement of CTGF production from a human carcinoma cell line transduced by HTLV-I tax gene, where the finding indicates the possible involvement of Tax in carcinogenesis. The second system, seeing IGFBP and VWC modules, could quantify not only CTGF, but also may be useful to analyze processed N-terminal fragments. The third system, utilizing capture and detection antibodies against the VWC module, was able to quantify the VWC module only, while it did not recognize full-length CTGF. Since CTGF is actually processed into subfragments, and functional assignment of each module is of interest, these systems are expected to contribute to the progress of CTGF investigations.

Antibodies, Monoclonal↗
PubMed1996

Human T-lymphotropic virus type I excretion and specific antibody response in paired saliva and cervicovaginal secretions.

Paired sera, salivas, and cervicovaginal secretions from 17 HTLV-I-infected women (10-75 years) were evaluated for total IgA, IgG, IgM, for IgA and IgG to whole HTLV-I lysate, for albumin, and for tax-rex proviral HTLV-DNA. IgG to HTLV-I were constantly detected, with much higher titers in serum (mean titer: 97,800) than in saliva (53) or in cervicovaginal secretions (216). IgA to HTLV-I were detected in only 12 (70%) sera, 6 (35%) salivas, and 8 (53%) cervicovaginal secretions, with higher titers in serum (75) than in saliva (8). Using the relative coefficient of excretion by reference to albumin, as well as the comparison of specific activities, the HTLV-I-specific IgG appeared primarily originating from serum, whereas IgA to HTLV-I were primarily locally produced. Salivary synthesis of IgG to HTLV-I occurred in both patients with a sicca syndrome attesting salivary glands impairment. Local excretions of total IgA, IgG, and IgM evaluated in body fluids were normal. HTLV DNA was detected in 4 (24%) salivas and in 3 (20%) cervicovaginal secretions, always in patients demonstrating local synthesis of HTLV-I-specific IgA or IgG. HTLV-I excretion elicits a weak local immune response to HTLV-I in saliva as well as in cervicovaginal secretions, which could be relevant for HTLV-I transmission via body fluids.

Adolescent↗
PubMed1996

Negative regulation of gene expression from the HTLV type II long terminal repeat by Rex: functional and structural dissociation from positive posttranscriptional regulation.

Regulation of human T cell leukemia virus type II (HTLV-II) gene expression by Rex is mediated by cis-acting elements in the 5' viral long terminal repeat (LTR). Rex acts posttranscriptionally to enhance cytoplasmic accumulation of incompletely spliced viral mRNAs encoding structural proteins. We report a distinct negative regulatory function mediated by Rex affecting expression from the viral 5' LTR. Using both LTR-driven CAT reporters and a full-length HTLV-II proviral construct, we demonstrate that Rex decreases total cellular levels of LTR-containing mRNA in a dose-dependent manner. Negative regulation is an independent function as demonstrated by structural and functional dissociation from Rex positive posttranscriptional regulation. This negative regulatory action was dependent on nuclear localization sequences, but did not require the previously defined Rex-responsive element (RxRE). Negative regulation was observed in T cell lines but not in B cell lines, suggesting the involvement of cell type-specific factors distinct from those involved in posttranscriptional regulation. An internal deletion mutant of Rex removing aa 38-80 retained the ability to repress, but did not posttranscriptionally increase expression, while negative regulation requires a previously uncharacterized carboxy-terminal region (aa 154-170). These findings suggest that Rex may serve two simultaneous functions: to decrease overall levels of transcribed viral mRNA, and to facilitate nuclear to cytoplasmic export of mRNAs encoding structural proteins. The negative regulatory function of Rex may play a role in viral latency.

Base Sequence↗
PubMed1998

Phylogenetic analysis of SIV and STLV type I in mandrills (Mandrillus sphinx): indications that intracolony transmissions are predominantly the result of male-to-male aggressive contacts.

Natural SIVmnd and STLVmnd infections of mandrills in a colony at the Centre International de Recherches Médicales de Franceville (CIRMF) in Gabon were investigated by genetic analysis to determine the extent of intracolony transmission. SIVmnd pol sequence analysis indicates that the six strains present in the colony belong to the SIVmnd lentivirus subgroup previously defined according to the only available prototype sequence (SIVmndGB1), which originated from the same colony. The intraanimal nucleotide diversity (1.1-3.1%) was similar in range to that reported in individuals infected by other HIV/SIVs. The interanimal diversity (0.5-4.3%) was not significantly different from that observed in each individual mandrill, indicating an epidemiological link among the SIVmnd isolates of distinct animals within the colony. Phylogenetic analysis of these isolates, together with seroepidemiological and behavior surveillance within the colony, indicates a predominant male-to-male transmission of SIVmnd that probably occurred during bouts of interanimal aggression. Moreover, our results suggest one case of vertical transmission of SIVmnd from a naturally infected founder female to one of her six offspring. The first genetic analysis of STLV isolates from mandrills is also reported here. Partial tax/rex sequences were used to evaluate the diversity between seven STLVmnd isolates and their phylogenetic relationships with other known strains of human and nonhuman primate T cell leukemia virus, types I and II (PTLV-I/II). They all belong to the PTLV-I subtype, but two genetically distinct STLVmnd groups were evidenced within the mandrill colony. The phylogenetic analyses of the STLVmnd isolates, together with seroepidemiological and behavior surveillance of the mandrills, indicate that intracolony transmissions of STLVmnd are also predominantly the result of male-to-male aggressive contacts.

Aggression↗
PubMed2004

Human T cell lymphotropic virus type I (HTLV-I) p12I is dispensable for HTLV-I transmission and maintenance of infection in vivo.

The function of the p12(I) protein of human T cell lymphotropic virus type I (HTLV-I) has been under debate. p12K (lysine) and p12R (arginine) variants of this protein at amino acid 88 and a shorter life of p12K had been reported by another group. Because HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients usually have a higher provirus load than asymptomatic HTLV-I carriers (ACs), and p12(I) had been suggested to confer a proliferative effect on HTLV-I-infected cells in vitro, it is possible that the relatively unstable p12K is less frequent in HAM/TSP patients than in ACs. To elucidate whether p12K and other alterations in the p12 gene were related to the outcome of HTLV-I infection, we sequenced the p12 gene in 144 HAM/TSP patients, 41 adult T cell leukemia (ATL) patients, and in 46 ACs. p12K was observed in only two HAM/TSP patients, but was not present in either ATL patients or ACs. Interestingly, a premature termination codon in the p12 was observed in 5.6% of HAM/TSP patients and in 4.9% of ATL patients but none was found in ACs. The p12 initiation codon was destroyed in one HAM/TSP patient. These HTLV-I variants with truncated p12 protein or with a destroyed initiation codon in the p12 gene appeared to have been transmitted in the subjects' families. These findings suggest that p12 is dispensable for the transmission and maintenance of HTLV-I infection, although it is premature to conclude that sequence varitation in the p12 gene is associated with differences in the outcome of HTLV-I infection.

Adult↗
PubMed2006

Distribution of human T cell lymphotropic virus type 1 (HTLV-1) subtypes in Brazil: genetic characterization of LTR and tax region.

We report the molecular and epidemiological characterization of 128 human T cell lymphotropic virus type 1 (HTLV-1) isolates from Brazilian patients with different clinical manifestations of the infection. Thirty-two percent of the patients were asymptomatic, 44% had HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 23% had adult T cell leukemia/lymphoma (ATLL). Phylogenetic analysis performed using part of the LTR region of the viral genome revealed that all Brazilian isolates belonged to the Cosmopolitan subtype, with the following distribution within the Transcontinental subgroup: 81.6% within the Latin American cluster and 15.8% outside the Latin American cluster. Two isolates belonged to the Japanese subgroup. Molecular analysis of the tax region showed a high nucleotide similarity ( approximately 99%) with 41 prototype sequences, including the ATK-1 isolate. The mean number of nucleotide substitutions ranged from 1 to 8. Five specific nucleotide substitutions, C7401T, T7914C, C7920T, C7982T, and G8231A, were highly conserved among the Brazilian isolates (79.6%), with a frequency ranging from 81.6% to 100% in the sample group and from 18.4% to 24.1% in the prototypes used, suggesting the existence of a molecular signature. These changes were not correlated with a specific clinical status of the patients and could be a molecular characteristic of the HTLV-1 strains that circulate in Brazil.

Adolescent↗
PubMed1992

Antisense oligonucleotide inhibition of bovine leukemia virus tax expression in a cell-free system.

Tax, the trans-activating protein of bovine leukemia virus, stimulates the long terminal repeat to promote viral transcription and also activates cellular genes that may be involved in tumorigenesis. To study Tax regulation, we identified antisense oligodeoxynucleotides that inhibit tax translation in rabbit reticulocyte lysate. Two antisense oligonucleotides directed toward the 5' end of tax RNA inhibited translation by 59% and 45%, when compared to the effect of a random sequence oligonucleotide. This inhibitory effect was independent of RNase H. In contrast, antisense directed at the middle of the tax RNA inhibited by only 12%, but, in the presence of RNase H, inhibited 38%. An antisense oligonucleotide directed at the 3' portion of tax RNA was not inhibitory and, in fact, stimulated translation. Identification of these inhibitory antisense sequences may allow elucidation of the biological role of Tax in BLV-persistent lymphocytosis and tumorigenesis.

Animals↗
PubMed2000

Enhanced invasion of Tax-expressing fibroblasts into the basement membrane is repressed by phosphorylated ascorbate with simultaneous decreases in intracellular oxidative stress and NF-kappa B activation.

Invasion of rat fibroblastic cells Rat-1 through Matrigel was shown to be promoted by transfection with tax gene of human T-cell leukemia virus type 1. We found that an oxidation-resistant type of vitamin C (Asc), Asc-2-O-phosphate (Asc2P), inhibited the invasion of the tax-transfected Rat-1 cells (W4 cells). Intracellular Asc (Ascin), after enzymatic dephosphorylation of administered Asc2P, was more abundant in W4 cells than in Rat-1 cells, and the ratio of dehydroascorbic acid versus Asc was increased in W4 cells but scarcely in Rat-1 cells, according to the enhanced level of intracellular reactive oxygen species (ROSin) in W4 cells. Asc2P notably repressed the increases in both ROSin and secretion of matrix metalloproteases (MMPs), but did not affect Tax protein expression in tax-transfectants. NF-kappa B activation, as evidenced by its translocation to the nucleus in W4 cells, was also repressed by Asc2P. Thus, the tax-promoted invasion together with the enhanced production of MMPs occurred with NF-kappa B activation and the increase in ROSin, both of which were effectively reduced by Asc2P. These findings indicate the therapeutic efficacy of Ascin-enriching agents for the prevention against tumor invasion in which ROSin plays a major role.

Animals↗
PubMed1996

Comparison of the antiviral efficacy of ribozymes and antisense RNA directed against bovine leukemia virus rex/tax.

Despite the theoretical attraction of ribozymes, which cleave their target RNA, as compared with antisense RNA, which only blocks translation, few studies have assessed the relative efficacy of ribozymes and antisense RNA directed against the identical target sequence. Previously, we described the efficacy of a hammerhead ribozyme targeted against rex/tax, a regulatory gene of bovine leukemia virus (BLV). In this study, we asked whether antisense RNA targeted against the same site would also be efficacious. BLV-infected bat lung cells were transfected with an antisense RNA-encoding plasmid under the control of sarcoma virus (RSV) promoter, and stable cell lines were selected. No inhibition of viral p24 expression was demonstrated in seven cell lines transfected with the antisense RNA targeted at the same site as the ribozyme or in three cell lines transfected with an antisense sequence targeted against the tax 5' initiation codon. Although in previous experiments antisense DNA oligonucleotides inhibited Tax expression in vitro, stably transfected plasmids encoding antisense RNA of the same sequence did not inhibit viral expression in BLV-infected cells in this study. These results suggest that in persistently infected cells producing high levels of BLV, the ribozyme is more effective than antisense RNA directed at rex/tax transcripts.

Animals↗
PubMed1991

High incidence of antibodies to HTLV-I tax in blood relatives of adult T cell leukemia patients.

Adult T cell leukemia (ATL) is caused by the human T cell leukemia virus type I (HTLV-I). Although the mechanisms of the leukemogenic process are unknown, the tax gene may have a role in this process. Because clustering occurs with HTLV-I and ATL, members of ATL families were examined for antibodies to the tax protein and compared with matched HTLV-I-positive blood donors. To investigate the antibody response to this protein, a plasmid, pBHX-4, was constructed to express a recombinant tax protein (r-tax). For ATL patients and their HTLV-I antibody-positive blood relatives, the rate of seroreactivity with the r-tax protein was 67.3% (35/52), compared with 51.6% (97/188) for HTLV-I antibody-positive control blood donors (P less than .05). The difference between direct offspring of ATL patients and matched HTLV-I blood donors was even greater (84.2% [16/91] vs. 44.2% [42/95]; P less than .005). Thus, tax antibody positivity in direct offspring of ATL patients may reflect differences in time or route of HTLV-I infection. Alternatively, it might reflect genetic differences in host susceptibility or virus strain.

Adolescent↗
PubMed1993

Reconstitution of the functional granulocyte macrophage colony stimulating factor promoter: evidence for distinct activation mechanisms that mediate the response to phorbol ester/calcium and human T cell leukemia virus type I Tax signals.

Functional elements in the promoter region of the mouse granulocyte-macrophage colony stimulating factor (GM-CSF) gene were assessed by constructing chimeric promoters linked to the bacterial chloramphenicol acetyltransferase (CAT) gene and by employing a transient transfection assay of human T cell leukemia Jurkat cells. We previously reported that CLE2/GC-box (at positions -95 to -73, which is homologous to the NF-kappa B binding site) and CLE0 (at positions to -40) of the mouse GM-CSF promoter are essential for transcriptional activation in response to phorbol-12-myristate-13-acetate (PMA)/calcium ionophore (A23187). Here we show that CLE2/GC-box and the NF-kappa B binding motif are functionally interchangeable and that CLE2/GC-box and CLE0 as a unit activate the basic GM-CSF promoter in response to PMA/calcium signals. This unit is also capable of activating heterologous promoters in response to PMA/calcium signals. In addition, we show that Tax, the trans-activator encoded by human T cell leukemia virus type I (HTLV-I), activates the GM-CSF promoter via CLE2/GC-box without the involvement of CLE0. These results indicate that PMA/A23187-dependent and Tax-dependent activation of the GM-CSF gene proceeds through distinct mechanisms.

Base Sequence↗
PubMed1999

Defective DNA repair in cells with human T-cell leukemia/bovine leukemia viruses: role of tax gene.

BACKGROUND: Human T-cell leukemia virus (HTLV)/bovine leukemia virus (BLV) group retroviruses, which cause hematopoietic cancers, encode a unique protein, Tax, involved in the transformation of infected cells. Our purpose was to determine whether the mechanism by which Tax protein induces transformation in HTLV- or BLV-infected cells involves DNA damage. METHODS: We used a micronucleus assay to measure chromosomal damage and alkali denaturation analysis to test host-cell DNA integrity in cells infected with HTLV, BLV, or simian T-lymphotropic virus or in cells transfected with the tax gene of HTLV or BLV. Controls included uninfected cells and cells infected with other oncogenic retroviruses or oncogenic DNA viruses. We used a plasmid reactivation assay to examine whether the damage might be due to the inhibition of DNA repair. To ascertain which of several repair pathways might be inhibited, chemical methods were used to selectively introduce lesions repaired by specific pathways into the reporter plasmid. RESULTS: The presence of Tax was associated with DNA damage. HTLV- or BLV-infected or tax-transfected cells showed normal ability to repair damage induced by deoxyribonuclease I or psoralen but markedly decreased ability to repair damage induced by UV light, quercetin, or hydrogen peroxide. CONCLUSIONS: These data suggest that the DNA repair pathway most inhibited by Tax is base-excision repair of oxidative damage. To our knowledge, this is the first report demonstrating inhibition of DNA repair by any retrovirus and suggests that this inhibition of DNA repair may contribute to the mechanism of cell transformation by the HTLV/BLV group of viruses.

Animals↗
PubMed2004

False-positive selection identified by ML-based methods: examples from the Sig1 gene of the diatom Thalassiosira weissflogii and the tax gene of a human T-cell lymphotropic virus.

Sexually induced gene 1 (Sig1) in the centric diatom Thalassiosira weissflogii is considered to encode a gamete recognition protein. Sorhannus (2003) analyzed nucleotide sequences of Sig1 using parsimony analysis and the maximum-likelihood (ML)-based Bayesian method for inferring positive selection at single amino acid sites and reported that positively selected sites were detected by the latter method but not by the former. He then concluded that for this type of study, the ML-based method is more reliable than parsimony analysis. Here we show that his results apparently represent false-positive cases of the ML-based method and that there is no solid evidence that this gene contains positively selected sites. We further demonstrate that in the tax gene of human T-cell lymphotropic virus type I (HTLV-I), all codon sites, including invariable sites, can be inferred as positively selected sites by the ML-based method. These observations indicate that the ML-based method may produce many false-positive sites. One of the main reasons for the occurrence of false positives is that in the ML-based method, codon sites are grouped into several categories, with different nonsynonymous/synonymous rate ratios (omegas), on a purely statistical basis, and positive selection is inferred indirectly by examining whether the average omega for each category is greater than 1. In parsimony analysis, however, the evolutionary change of nucleotides at each codon site is examined. For this reason, parsimony-based methods rarely produce false positives and are safer than ML-based methods for detecting positive selection at individual codon sites, although a large number of sequences are necessary.

Bayes Theorem↗