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At least 127 records · Page 7Linked to original sources

PubMed1990

Functional comparison of transactivation by human retrovirus rev and rex genes.

The effect of rev-responsive element deletion on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) gene expression was examined. The phenotypes of HIV-1 and HIV-2 provirus DNAs lacking the rev-responsive element, as determined by transfection experiments, were indistinguishable from those of virus DNAs carrying rev gene mutations. By using rev-response elements derived from these two viruses, we developed two monitoring systems to evaluate the functionality of HIV-1 rev, HIV-2 rev, and human T-lymphotropic virus type I rex. In both systems, HIV-1 rev and human T-lymphotropic virus type I rex transactivated HIV-2 very efficiently. On the contrary, HIV-2 rev and human T-lymphotropic virus type I rex were poor activators of HIV-1. No functional replacement of rex by HIV-2 rev was observed.

Blotting, Northern↗

PubMed1991

Transdominant repressors for human T-cell leukemia virus type I rex and human immunodeficiency virus type 1 rev function.

Human T-cell leukemia virus type I (HTLV-I) encodes a 27-kDa trans-acting gene product (Rex) which is involved in the regulated expression of transcripts coding for the viral structural proteins. We used oligonucleotide-directed mutagenesis to generate a series of mutant HTLV-I rex genes. Transient expression experiments demonstrated that 3 of 28 mutant proteins are functionally inactive on the homologous HTLV-I rex response element, whereas an additional 2 mutant proteins are functionally inactive on the heterologous human immunodeficiency virus type 1 rev response element. One of these mutants is able to suppress the function of the wild-type HTLV-I Rex protein in trans on the homologous rex response element sequence. Furthermore, all of these mutants are able to inhibit Rex function on the heterologous rev response element sequence. Intriguingly, only three of these mutants are able to inhibit the human immunodeficiency virus type 1 Rev protein in a dominant-negative manner.

Amino Acid Sequence↗

PubMed1991

Effector domains of human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex are functionally interchangeable and share an essential peptide motif.

The human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex transactivators are posttranscriptional regulatory proteins that promote retroviral gene expression by interacting with specific viral mRNAs. Rev and Rex have markedly dissimilar amino acid sequences and RNA target specificities but are thought to act through the same cellular pathway. In this report, we demonstrate that short peptide domains which are required for effector activity in Rev and Rex are functionally interchangeable. Activity of these effector domains depends upon a previously unrecognized tetrapeptide motif that is present in both Rev and Rex and also in analogous proteins from other complex retroviruses. The conserved effector motif may mediate essential interactions of Rev, Rex, and other transactivators of this type with a common cellular cofactor.

Amino Acid Sequence↗

PubMed1991

Functional mapping of the human immunodeficiency virus type 1 Rev RNA binding domain: new insights into the domain structure of Rev and Rex.

Expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the direct interaction of the viral trans-activator protein Rev with its cis-acting RNA sequence (Rev-response element [RRE]). A stretch of 14 amino acid residues of the 116-amino-acid Rev protein is sufficient to impose nucleolar localization onto a heterologous protein. Our results demonstrated that these same amino acid residues confer Rev-specific RRE binding to the heterologous human T-cell leukemia virus type I Rex protein. In addition, our results indicated that amino acids distinct from the nuclear localization signal are important for Rex-specific RRE RNA binding.

Amino Acid Sequence↗

PubMed1991

Effects of chimeric mutants of human immunodeficiency virus type 1 Rev and human T-cell leukemia virus type I Rex on nucleolar targeting signals.

Two chimeric mutant genes derived from rev of human immunodeficiency virus type 1 and rex of human T-cell leukemia virus type I were constructed to investigate the functions of the nucleolar-targeting signals (NOS) in Rev and Rex proteins. A chimeric Rex protein whose NOS region was substituted with the NOS of Rev was located predominantly in the cell nucleolus and functioned like the wild-type protein in the Rex assay system. However, a chimeric Rev with the NOS of Rex abolished Rev function despite its nucleolar localization. This nonfunctional nucleolar-targeting chimeric protein inhibited the function of both Rex and Rev. In the same experimental conditions, this mutant interfered with the localization of the functional Rex in the nucleolus.

Amino Acid Sequence↗

PubMed1991

Mutational analysis of the human T-cell leukemia virus type I trans-acting rex gene product.

Expression of the human T-cell leukemia virus type I (HTLV-I) rex gene is a prerequisite for the expression of the retroviral structural proteins. We have generated internal deletion mutants of this 27-kDa nucleolar trans-acting gene product to define functional domains in the Rex protein. The phenotype of the various mutant proteins was tested on the homologous HTLV-I rex response element sequence and the heterologous human immunodeficiency virus type 1 (HIV-1) rev response element sequence. Our results indicate that a region between amino acid residues 55 and 132 in the 189-amino-acid Rex protein is required for Rex-mediated trans activation on both retroviral response element sequences. In addition, substitution of the Rex nuclear localization signal by a sequence of the HIV-1 rev gene product targets the Rex protein to the correct subcellular compartment required for Rex function.

Amino Acid Sequence↗

PubMed1992

Evolutionary insights on the origin of human T-cell lymphoma/leukemia virus type I (HTLV-I) derived from sequence analysis of a new HTLV-I variant from Papua New Guinea.

Recent studies have established the presence of human T-cell lymphoma/leukemia virus type I (HTLV-I) in Melanesia. An HTLV-I strain, PNG-1, has now been isolated from a healthy member of the Hagahai, a remote, recently contacted group in Papua New Guinea. To further characterize PNG-1, we employed polymerase chain reaction amplification with subsequent cloning and sequencing of amplified products. Sequence analyses of amplified regions of pol, env, and pX genes of this variant indicate marked heterogeneity (approximately 7%) from prototype HTLV-I. Based on available sequence data, PNG-1 is distinct from all other known HTLV-I strains and diverges from the common ancestor of HTLV-I prior to prototype isolates. The data also suggest, therefore, that HTLV-I originated in the Indo-Malay region rather than Africa.

Amino Acid Sequence↗

PubMed1993

Complete nucleotide sequence of an Amerindian human T-cell lymphotropic virus type II (HTLV-II) isolate: identification of a variant HTLV-II subtype b from a Guaymi Indian.

The complete nucleotide sequence of a human T-cell lymphotropic virus type II (HTLV-II) isolate from a Panamanian Guaymi Indian was determined and analyzed. When this new viral isolate (HTLV-IIG12) was compared with prototypic HTLV-IIMoT, the overall nucleotide sequence similarity was 95.4%, while the predicted amino acid sequence similarity was 97.5%. Although the overall percentage of nucleotide and amino acid identity with prototypic HTLV-IIMoT (subtype a) was high, HTLV-IIG12 displayed several distinctive features that defined it as an HTLV-II subtype b. However, there were several characteristics unique to this isolate, which included a cluster of nucleotide substitutions in the pre-gag region and changes in restriction enzyme sites within the pre-gag region and the gag, pol, env, and pX genes. In addition, two nucleotide changes in the C terminus of the Tax protein coding sequence inserted an Arg residue for a stop codon and appeared to result in a larger tax gene product in HTLV-IIG12. Although the HTLV-IIG12 isolate appears to be a variant of the prototypic HTLV-IIb, this information represents the first complete nucleotide sequence of any HTLV-II subtype b. These data will allow further studies on the evolutionary relationships between the HTLV-II subtypes and between HTLV-I and HTLV-II.

Amino Acid Sequence↗

PubMed1993

Transcomplementation of simian immunodeficiency virus Rev with human T-cell leukemia virus type I Rex.

A molecular clone of the simian immunodeficiency virus SIVSMM isolate PBj14, lacking the ATG initiation codon for Rev protein (PBj-1.5), did not produce virus or large unspliced or singly spliced viral RNA upon transfection of HeLa cells. Low but significant levels of virus and large viral RNA production were observed upon transfection of PBj-1.5 into HeLa Rev cells expressing the rev gene of human immunodeficiency virus type 1. Furthermore, abundant virus and large viral RNA production occurred upon transfection of PBj-1.5 into HeLa Rex cells expressing the rex gene of human T-cell leukemia virus type I. Virus produced from HeLa Rex and HeLa Rev transfections was infectious, produced large amounts of virus, and was cytopathic for Rex-producing MT-4 cells. In contrast, no or only low levels of virus production were observed upon infection of H9 cells. These studies show that a defective SIV rev gene can be transcomplemented with human immunodeficiency virus type 1 Rev and with high efficiency by human T-cell leukemia virus type I Rex, and they suggest that rev-defective viruses could serve as a source for production of a live attenuated SIV vaccine.

Amino Acid Sequence↗

PubMed1994

Transcriptional suppression of the human T-cell leukemia virus type I long terminal repeat occurs by an unconventional interaction of a CREB factor with the R region.

To analyze regulation of the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR), cell lines were generated from LTR-tax x LTR-beta-galactosidase (beta-Gal) doubly transgenic mouse fibroblastic tumors. The HTLV-I LTR directs expression of both the tax and lacZ genes, and Tax up-modulates both promoters in primary cells. However, once cells were transformed by tax, beta-Gal but not tax expression was suppressed. Supertransformation of these cells with v-src suppressed both beta-Gal and tax expression. This suppression was reversed by treatment with the tyrosine kinase inhibitor herbimycin A or protein kinase A inhibitor H8. Electrophoretic mobility shift assays demonstrated augmented binding in the R but not U3 region. This binding was competitively inhibited by a high-affinity CREB oligodeoxynucleotide and super-shifted with a specific CREB antibody. Treatment of cells with the cyclic AMP analog dibutyryl cyclic AMP also transiently increased the R region binding dramatically. In vitro DNase I footprint analysis identified a protein-binding sequence in the R region which corresponded with suppression. However, this target sequence lacked a conventional CREB-binding site. A 70.5-kDa DNA-binding protein was partially purified by affinity chromatography, along with a 49-kDa protein which reacted with CREB-specific sera. These data demonstrate that HTLV-I LTR suppression is associated with CREB factor binding in the R region, probably by direct interaction with a 70.5-kDa protein, and provide a novel mechanism for maintenance of viral latency.

Animals↗

PubMed1996

HTLV Tax gene expression in patients with lymphoproliferative disorders.

AIMS: To study the expression of the human T lymphotropic virus (HTLV) Tax gene in peripheral blood mononuclear cells. METHODS: Blood was collected from 72 patients with lymphoproliferative disorders. Serum from all patients was assayed for antibodies directed against HTLV-I structural proteins by ELISA and western blotting. RNA was purified from fresh blood cells and amplified by reverse transcription polymerase chain reaction (RT-PCR). After Southern blotting, the PCR products were hybridised with a 32P end-labelled probe specific for the Tax gene. RESULTS: All samples were seronegative. A specific band for the Tax gene was found in five samples. Each of the patients positive for Tax gene expression had a different type of lymphoproliferative disorder. CONCLUSIONS: Infection by HTLV-I cannot be assessed solely by immunological assays, particularly when only disrupted virions are used. Sensitive molecular biology assays are essential for detecting viral gene expression in fresh blood cells.

Adolescent↗

PubMed1995

The cutaneous T cell lymphoma, mycosis fungoides, is a human T cell lymphotropic virus-associated disease. A study of 50 patients.

For nearly two decades it has been suspected that the cutaneous T cell lymphoma, mycosis fungoides (MF), and its leukemic variant, the Sézary syndrome, are caused by the human T lymphotropic virus (HTLV-I/II). Arguments against this concept included the finding that only a small number of MF patients have antibodies to HTLV-I/II and that attempts to detect proviral sequences by mere Southern hybridization of extracted DNA usually met with failure. However, we have reported repeatedly that HTLV-like particles emerge in blood mononuclear cell (PBMC) cultures of practically all patients with this disease. In several instances, the particles were identified as HTLV by immunoelectron microscopy as well as biomolecular analysis. With the assumptions that the virus in MF patients may have become detection by Southern hybridization alone, the extracts of freshly isolated PBMC of 50 consecutive patients were subjected to combined PCR/Southern analysis. Here we report the presence of HTLV pol and/or tax proviral sequences in 46 out of 50 (92%) of the patients tested. In addition, five of the patients, who lacked antibodies to HTLV-I/II structural proteins, were found to be seropositive for tax. It thus seems reasonable to conclude that MF/Sézary syndrome is an HTLV-associated disease and that lack of an immune response does not preclude infection with this type of virus.

Adult↗

PubMed1989

Immortalization of rat spleen and thymus T cells by human T-cell leukemia virus type I.

Co-cultivation of thymus and spleen cells of Fisher and Lewis rats with lethally irradiated MT-2 cells harboring human T-cell leukemia virus type I (HTLV-I) resulted in the establishment of lymphoid cell lines, FIRT-1, FIRS-1, LERT-1, and LERS-1, respectively. Cells of these cell lines had rat T-cell characters as demonstrated by the positive reaction to monoclonal antibodies (MAbs) to rat T cell antigens (Thy 1 and pan T). They lacked surface immunoglobulins and strongly expressed rat interleukin-2 receptor antigen (Tac) and Ia antigen. Karyotypic analysis revealed that they had the normal rat karyotype in early cultures, but showed marked aneuploidy after long cultivation. None of them expressed HTLV gag proteins (p19 and p24) or virus particles, but they contained HTLV-I proviral DNA monoclonally and weakly expressed pX gene products (p40x). They were not transplantable into syngeneic newborn rats.

Animals↗

PubMed2006

Role of neuronal interferon-gamma in the development of myelopathy in rats infected with human T-cell leukemia virus type 1.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of not only adult T-cell leukemia but also HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among the rat strains infected with HTLV-1, chronic progressive myelopathy, named HAM rat disease, occurs exclusively in WKAH rats. In the present study, we found that HTLV-1 infection induces interferon (IFN)-gamma production in the spinal cords of HAM-resistant strains but not in those of WKAH rats. Neurons were the major cells that produced IFN-gamma in HTLV-1-infected, HAM-resistant strains. Administration of IFN-gamma suppressed expression of pX, the gene critically involved in the onset of HAM rat disease, in an HTLV-1-immortalized rat T-cell line, indicating that IFN-gamma protects against the development of HAM rat disease. The inability of WKAH spinal cord neurons to produce IFN-gamma after infection appeared to stem from defects in signaling through the interleukin (IL)-12 receptor. Specifically, WKAH-derived spinal cord cells were unable to up-regulate the IL-12 receptor beta2 gene in response to IL-12 stimulation. We suggest that the failure of spinal cord neurons to produce IFN-gamma through the IL-12 pathway is involved in the development of HAM rat disease.

Animals↗

PubMed1997

Adult T-cell leukemia/lymphoma with features of CD30-positive anaplastic large cell lymphoma--a case report.

We experienced a 58-year-old Korean man with adult T-cell leukemia/lymphoma with features of histologically anaplastic large cell lymphoma involving the skin and testis. The patient had cutaneous nodules in both extremities and a palpable right testicular mass. Right orchiectomy was performed and specimens of removed testicle and skin nodules showed immunohistologically anaplastic large cell lymphoma with T-cell phenotype, and CD30 antigen was positive. A human T-cell lymphotropic virus type 1 (HTLV-1) antibody titer was over 1 : 256 and integration of HTLV-1 proviral DNA pX gene was identified in the peripheral blood mononuclear cells and lymphoma tissue by polymerase chain reaction. Peripheral blood and bone marrow did not show any evidence of characteristic neoplastic T-cells.

Diagnosis, Differential↗

PubMed1995

Sequence and phylogenetic analyses of human T cell lymphotropic virus type 1 from a Brazilian woman with adult T cell leukemia: comparison with virus strains from South America and the Caribbean basin.

Human T cell lymphotropic virus type 1 (HTLV-1) is endemic in South America and the Caribbean basin. To clarify the genetic and phylogenetic relationship between an HTLV-1 strain isolated from a Brazilian woman with adult T cell leukemia and viral isolates from elsewhere in South America and from other geographic regions, selected regions of the gag, pol, env, and pX genes were amplified and directly sequenced. The overall sequence similarities between the Brazil-R-1 strain and the Japanese prototype ATK strain were 98.7% based on 1,295 nucleotides and 99.1% based on 429 amino acids. Phylogenetic analysis indicated that strain Brazil-R-1 clustered with other Brazilian and South American HTLV-1 isolates and was more closely related to Caribbean isolates from Martinique and Guadeloupe than to virus strains from other geographic regions. These data suggest a common source of HTLV-1 infection in the Caribbean basin and South America.

Amino Acid Sequence↗

PubMed1997

Laboratory characterization of human T cell lymphotropic virus types 1 (HTLV-1) and 2 (HTLV-2) infections in blood donors from Sao Paulo, Brazil.

Serologic screening for human T cell lymphotropic virus types 1/2 (HTLV-1/2) infection in blood donors has been recently introduced in Brazil. Analysis of 351,639 blood donations in Sao Paulo from January 1992 to October 1993 identified 1,063 positive (0.30%) and 2,238 indeterminate (0.63%) samples based on serologic confirmation using a 21e Western blot. A detailed analysis (serologic, molecular, and virologic), based on a laboratory diagnostic algorithm for characterization of HTLV-1 and HTLV-2 infections was undertaken in 50 seropositive or seroindeterminate blood donors. Modified serologic assays (2.3 Western blot that incorporate type-specific recombinant peptides) performed in 29 HTLV-1/2 positive and 21 HTLV-1/2 indeterminate donors with the 21e Western blot identified 25 as infected with HTLV-1, four with HTLV-2, five with untypable HTLV-1/2, 15 as HTLV-1/2 indeterminate, and one as seronegative. Polymerase chain reaction (PCR) analysis using DNA amplification of proviral pol and tax sequences from peripheral blood mononuclear cells confirmed HTLV-1 and HTLV-2 infections in all 2.3 Western blot seropositive donors; of the five serologically untypable donors, three were confirmed to be HTLV-1 positive, one HTLV-2 positive, and one negative by PCR. All of the seroindeterminate donors were also negative by PCR. Furthermore, HTLV-1 could be isolated in cocultures from 10 of 18 infected donors. Cell lines developed from two HTLV-1-infected donors were of T cell phenotype (CD2+, CD3+), exhibiting surface markers of activated CD4 cells (CD4+ CD25+ HLA-DR+). Thus, we provide evidence for the high seroprevalence of HTLV infection in blood donor population in Sao Paulo, Brazil compared with North American donors and propose a comprehensive serologic and genotypic diagnostic algorithm for HTLV-infected donors that has strong implications for counseling of these individuals.

Antigens, CD↗

PubMed1992

Human T-cell leukemia virus type I as agent inducing genetic changes in infected human lymphocytes.

Sera and DNA samples, including cord blood, were examined from six members of a three-generation family suspected of being carriers of HTLV-I. Serum antibodies to HTLV-I were detected by Western blot analysis more clearly in adults than in children. DNA sequences related to HTLV-I-gag and -tax, but not -pol genes were detected more clearly in specific PCR products of DNA of adults than those of children, and of the cord blood by Southern hybridization analysis. HTLV-I-related DNA sequences were also detected in some HTLV-I-seropositive as well as seronegative patients with T-cell dyscrasia and with other diseases, including carcinoma. Frequencies of chromosome abnormalities were found to be significantly higher in lymphocytes of HTLV-I-seropositive persons than in those of HTLV-I-seronegative persons. Immortalization of cultured lymphocytes following infection with HTLV-I was found to be accompanied by chromosome and gene rearrangements. Transformation of these cells following treatment with carcinogens was found to be accompanied by additional chromosome rearrangements. These results suggest that some persons may be born with HTLV-I-related sequences that are repressed in childhood. Repeated expression of their products may result not only in the host antibody response but also in increased chromosomal instability and in increased risk for further genetic changes of carrier cells when exposed to environmental carcinogens.

Adolescent↗