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PubMed1992

[Epidemiology of HTLV-I carriers in Hirado Island and virological and immunological investigation of HTLV-I associated pulmonary disease].

Adult T-cell leukemia (ATL) is endemic in Kyushu. Our study at Hirado island in Nagasaki prefecture revealed a higher incidence (35.9%) of HTLV-I carriers in villages with fishing than in those without (16.5%). HTLV-I carriers showed a higher incidence of abnormal findings on chest roentgenogram (21.7%) than non-carriers (16.5%), but most were lesions of old pulmonary tuberculosis and pleural thickening. Virological and immunological investigations were performed for 10 HTLV-I carriers, 3 patients with HTLV-I associated myelopathy (HAM), and 3 patients with ATL to determine the presence of HTLV-I associated pulmonary disease. In HAM patients, there were high titers of anti HTLV-I antibody, positive IgA reaction to HTLV-I, and an increase in interleukin-2 receptor (IL-2)-positive T-cells in the peripheral blood; and lymphocytosis and an increase in IL-2-positive T-cells in the bronchoalveolar lavage fluid (BALF). Virological examination showed the presence of pX gene and tax1/rex1 mRNA in the peripheral blood and BALF. Similar immunological and virological findings in 2 of 10 carriers suggested the presence of HTLV-I associated pulmonary disease.

Aged↗
PubMed1991

Semiquantitative analysis of integrated genomes of human T-lymphotropic virus type I in asymptomatic virus carriers.

A semiquantitative estimation of human T-lymphotropic virus type I (HTLV-I) integration by peripheral blood mononuclear cells (PBMC) was performed. Genomic DNA samples derived from 134 HTLV-I carriers were subjected to 40 or 60 cycles of the polymerase chain reaction to amplify the pol region of HTLV-I. The HTLV-I genome was detected by dot hybridization using a 32P-labeled oligonucleotide probe for the pol region. The radioactivity of hybridized dot membranes was then counted with an RI Imaging System (Ambis Inc, San Diego, CA) and the HTLV-I genome dose was determined by comparison with standard curve for serially diluted HTLV-I genome-positive DNA. A wide range of variation of HTLV-I genome integration was observed. When the integrated genome dose was calculated as the number of HTLV-I copies per 100 PBMC, 7 carriers (5%) had more than 10 copies, 56 (42%) had 1 to 10 copies, 46 (34%) had 0.1 to 1 copy, and 24 (18%) had less than 0.1 copy. In one sample, the HTLV-I genome was undetectable, which may indicate that the integrated genome was present at less than 0.01 copies per 100 PBMC. Age- or sex-related variations in the distribution of individuals with different HTLV-I genome were rather limited. However, carriers with a high level of the HTLV-I genome were always more than 30 years old and were predominantly male (six of seven).

Aging↗
PubMed1988

Expression, release, and characterization of soluble human T-lymphotropic virus-I (HTLV-I) antigens from an infected cell line.

The Human T-lymphotropic virus type I (HTLV-I) infected cell line MT-2 was studied to obtain HTLV-I or related proteins for the purpose of producing an effective vaccine for HTLV-I infection. The cells were characterized as to HTLV-I antigen expression during the cell cycle and antigens released into the culture fluids. MT-2 cell grown in fetal calf supplemented media produced more HTLV-I related antigens during the G2/M phase of the cell cycle. To determine the conditions for maximal release and harvest of HTLV-I associated proteins, the MT-2 cells were grown in RPMI 1640 medium supplemented with serum-free medium. Cell- and virus-free supernatants were collected on day 4, lyophilized, and concentrated 50-fold. The proteins in these supernatants were characterized using SDS-PAGE and western blot using rabbit anti-HTLV-I sera and human adult T-cell leukemia sera. The western-blot analysis indicated that the supernatants obtained from the MT-2 cells grown in serum-free supplemented medium contained detectable amounts of proteins which reacted with human ATL and rabbit anti-HTLV-I sera. The molecular weights of these proteins observed are 68kd, 46kd, 28kd, 24kd, 19kd, and 15kd indicating that gag, env, and pX gene products are present.

Blotting, Western↗
PubMed1994

[The nervous system involvement in human retroviral infection].

Human T-lymphotropic virus type I (HTLV-I) is a pathogenic retrovirus associated with a chronic progressive myelopathy, termed HTLV-I-associated myelopathy (HAM). A chronic inflammatory process has been implicated in HAM by a pathological study, but the exact mechanism still remains to be elucidated. Our quantitative polymerase chain reaction study indicated that the large increase in the HLTV-I proviral DNA in peripheral blood is associated with the development of HAM. The nucleotide sequence analysis of HTLV-I in central nervous system (CNS) tissue of HAM patients revealed that the sequences of HTLV-I genome were heterogenous in all cases, and that the pX-defective mutants were found frequently in the CNS. Thus, HTLV-I exists as quasispecies in vivo, as shown in the case of human immunodeficiency virus. It is possible that the HTLV-I pX microvariants contribute to the neural damage, since the pX gene products are essential for the transactivation of various cellular genes as well as for viral replication.

Animals↗
PubMed1993

The Sukhumi primate monkey model for viral lymphomogenesis: high incidence of lymphomas with presence of STLV-I and EBV-like virus.

T-cell leukemia virus-like proviral sequences (STLV-I) as well as EBV-like sequences were detected in PBLs and tissues of non-human primates (Papio hamadryas baboons, Green monkeys and Macaca arctoides; Sukhumi Primate Center/Georgia) by PCR. Surprisingly, two different types of STLV-I within Papio hamadryas baboons were found. One of its represents the baboon prototype STLV-I-Su described earlier, present in lymphomatous baboons from the "high-lymphoma stock", which shows about 83% homology to HTLV-I and 85% to STLV-I in the env and tax genes. The inter-individual variability within this subtype is very low (about 1% in the tax gene). The second subtype was mainly found in asymptomatic animals from the control colony and showed in the env gene 95% homology to HTLV-I, but only 82% to the prototype baboon sequence. The presence of two subtypes within the Sukhumi baboon population might be interesting in respect to the inoculation experiments with human leukemic blood and to possible interspecies transmissions. The nature of the Herpes Papio-virus was elucidated as EBV-like and the homology to the human EBV was > 90% in the polymerase gene. The homologies between different monkey species were between 92 and 96% and also here two subtypes within the baboons were detected. This is the first direct demonstration by sequencing that the Herpes Papio virus is closely related to EBV. For further studies of this animal model, rabbits were inoculated with cells originated from lymphomatous baboons and macaques. The rabbits developed generalized lymphomas lethal within 1-2 months. EBV-like and STLV-I-like sequences could be detected by PCR and sequencing showed 99-100% identity to the inoculum, indicating in fact the transmission from monkey to rabbit. These animal models seem to be very suitable for the elucidation of the pathogenesis of human HTLV-I associated T-cell leukemia/lymphoma and might be further on used for therapeutical and preventative studies.

Animals↗
PubMed1993

HTLV-1 sequences in lymphocytes of a patient with non-tropical spastic tetraparesis and her asymptomatic husband.

We describe a 65-year-old woman born and living in Northern Italy affected by non tropical spastic tetraparesis and her asymptomatic husband presenting HTLV-1 sequences in their lymphocytes detected by polymerase chain reaction (PCR). We discuss the significance of the case and the mechanism involved in HTLV-1 infection and the relationship with neurological disorders, stressing that this case is the first reported in Italy.

Blotting, Southern↗
PubMed1995

Molecular phylogeny and dissemination of human T-cell lymphotropic virus type I viewed within the context of primate evolution and human migration.

A renewed interest in the emergence and evolution of the primate T-cell lymphotropic viruses has followed the discovery of genetically distinct variants of human T-cell lymphotropic virus type I (HTLV-I) in Melanesia and Australia. Phylogenetic trees based on selected regions of the gag, pol, env and pX genes of HTLV-I from widely separated geographic regions and of simian T-cell lymphotropic virus type I (STLV-I) from African and Asian catarrhines, constructed using the neighbor-joining and maximum parsimony methods, indicated that the Australo-Melanesian and cosmopolitan strains of HTLV-I have evolved along separate geographically dependent lineages, with African STLV-I strains clustering with cosmopolitan HTLV-I strains and Asian STLV-I strains diverging from the common ancestral virus before the Australo-Melanesian HTLV-I strains. When viewed within the context of non-human primate evolution and human occupation of Australia and Melanesia, the rate of molecular change of HTLV-I and STLV-I is approximately 2.5-6.8 x 10(-7) substitutions per site per year. Overall, the sequence and phylogenetic analyses are in accord with interspecies virus transmission among non-human primates, as well as between non-human primates and humans, with independent evolution of HTLV-I in Southeast Asia and in Africa, and with dissemination of HTLV-I by forced or voluntary movements of human populations. The immunosuppressive and T-cell activation properties of HTLV-I places at added risk these Australian Aboriginal and Melanesian populations, some of which are in imminent threat of infection with human immunodeficiency virus type 1.

Africa↗
PubMed1986

Monoclonal antibody NCC-pX-1G reactive with gene products coded from X regions of human T-cell leukemia virus.

Monoclonal antibody NCC-pX-1G (IgG1, kappa) was obtained by the hybridoma technique by immunization of mice with the C-terminal 54 amino acids of the pX protein, made from the 3'-terminal portion of the pX gene conjugated with bovine growth hormone gene transfected in E. coli. NCC-pX-1G recognized 41 kilodalton pX protein of HTLV-I, and immunocytochemically stained HUT102 and other HTLV-I-infected cell lines, but no reaction was observed with non-HTLV-I-infected cell lines or normal human tissue cells.

Animals↗
PubMed1991

Immunogenicity of human T cell leukemia virus type-I (HTLV-I) antigens for cytotoxic T lymphocytes in the rat system.

We showed previously that WKA (rat MHC, RT-1k) and DA (RT-1a) rat CTL specific for human T cell leukemia virus type-I (HTLV-I) recognized the gag and pX gene-encoded Ag. In the present study, we explored HTLV-I Ag recognized by CTL from other MHC genotype (RT-1l) rats, LEW and F344, and examined whether HTLV-I Ag expressed by recombinant vaccinia viruses (rVV) could prime WKA and LEW rats for HTLV-I-specific CTL. Upon priming in vivo and repetitive stimulation in vitro with HTLV-I+ syngeneic T cells, HTLV-I-specific CD8+ CTL were demonstrated in LEW and F344 rat spleen cell cultures. Interestingly, these CTL were directed against HTLV-I env and pX gene products. Immunization of LEW and WKA rats with the env and gag gene-expressing rVV, respectively, resulted in generation of HTLV-I-specific CD8+ CTL. However, a pX-gene expressing rVV failed to prime either rat strain. In addition, HTLV-I-specific CD8+ CTL from F1 hybrid (WKA x LEW) rats generated by immunization and restimulation with HTLV-I+ syngeneic T cells showed gag and pX Ag specificity on WKA rat cells and env and pX Ag specificity on LEW rat cells. These results suggest that immunogenicity of HTLV-I gag and env Ag in induction of HTLV-I-specific CTL varies depending on MHC, and that the pX Ag expressed by rVV is not a potent immunogen for rats.

Animals↗
PubMed1994

[Detection of HTLV-1 provirus DNA in T-cell neoplasms].

Using polymerase chain reaction (PCR) amplification and Southern hybridization, gag, pol, env and pX region genes of HTLV-1 provirus were detected in T-cell malignancy such as adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides in leukemic phase (MF) and, CD8-leukemia. The gag, pol, and/or env regions, were not amplified in some cases of ATLL, which was considered to be induced by mutation, but not deletion. However, the pX-1 and pX-2 regions could be amplified in all cases examined. As it is suggested that the pX gene plays an important role in leukemogenesis, the mutation may not occur in this region gene. Interestingly, the pX-2 was amplified in the cases with MF and CD8-leukemia as well. The amplified products were hybridized to the HTLV-1 pX sequence, even though the products contained DNA fragments with a size larger than expected as well as those of an expected size. These results indicated the possibility that the virus having sequence identical with HTLV-1 pX is integrated in the tumor cells of MF and CD8 leukemia.

Base Sequence↗
PubMed1998

Genes in the pX region of human T cell leukemia virus I influence Vav phosphorylation in T cells.

Human T cell leukemia virus I (HTLV-I) causes acute leukemic disease in a low percentage of infected individuals through obscure mechanisms. Our studies compare two rabbit HTLV-I-infected T cell lines: one, RH/K34, causes lethal experimental leukemia and the other, RH/K30, mediates asymptomatic infection. We show herein that the product of the protooncogene vav is constitutively Tyr-phosphorylated in RH/K34 but not in RH/K30. A role for the retrovirus in phosphorylation of Vav was assigned by transfection experiments with molecular clones of HTLV-I derived from the two lines. The HTLV-I molecular clone from RH/K30, but not that from RH/K34, down-regulates Vav phosphorylation in a Herpesvirus ateles-transformed T cell line. Use of recombinant virus clones revealed that a pX region sequence differing by two nucleotides between the two clones mediates this down-regulation. Because Vav is involved in T cell signaling and Vav phosphorylation occurs upon activation of T cells, control of the activation state of Vav by viral proteins may relate to the leukemogenic potential of certain HTLV-I-infected cells.

Animals↗
PubMed1987

Transcriptional (p40x) and post-transcriptional (p27x-III) regulators are required for the expression and replication of human T-cell leukemia virus type I genes.

The pX sequence of human T-cell leukemia virus type I codes for three products: p40x, p27x-III, and p21x-III. p40x is a transcriptional trans-activator that activates not only the viral long terminal repeat but also cellular genes for interleukin 2 and its receptor. p27x-III and p21x-III are not required for transcriptional activation, and their functions were unknown. Cotransfection experiments with defective human T-cell leukemia virus type I proviruses and various pX expression plasmids revealed that p27x-III, in addition to p40x, was required for gag gene expression. Furthermore, it was shown that p27x-III induced accumulation of a high level of unspliced viral gag mRNA. These results indicate that p27x-III is a post-transcriptional modulator of viral RNA whose transcription has been fully activated by p40x.

Cell Line↗
PubMed1997

The hepatitis B virus X protein enhances the DNA binding potential and transcription efficacy of bZip transcription factors.

The hepatitis B virus X protein interacts with the basic-region, leucine zipper protein (bZip) domain of cAMP response element-binding protein increasing its affinity for the cAMP response element site in vitro and its transcriptional efficacy in vivo (Williams, J. S., and Andrisani, O. M. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 3819-3823). Here we examine pX interactions with bZip transcription factors ATF3, gadd153/Chop10, ICER IIgamma, and NF-IL6. We demonstrate direct interactions in vitro between pX and the bZip proteins tested. In contrast MyoD and Gal4(1-147) fail to interact with pX. We also demonstrate by the mammalian two-hybrid assay the direct interaction of pX with cAMP response element- binding protein, ICER IIgamma, ATF3, and NF-IL6 in hepatocytes. In addition, pX increases the DNA binding potential of bZip proteins for their cognate DNA-binding site in vitro. In transient transfections in hepatocytes (AML12 cell line), pX increases the transcriptional efficacy of the bZip transcription factors. NF-IL6-mediated transcriptional activation is enhanced 3-fold by pX. Most interestingly, pX augments the repression mediated by bZip repressors ATF3 and ICER IIgamma, by 6- and 7-fold, respectively, demonstrating for the first time the involvement of pX in gene repression. We conclude that pX is an enhancer of the DNA binding potential of bZip transcription factors, thereby increasing the transactivation or repression efficacy of bZip-responsive genes.

Animals↗
PubMed1998

Human T-cell leukemia virus type 1 pX-I and pX-II open reading frames are dispensable for the immortalization of primary lymphocytes.

Human T-cell leukemia virus type 1 (HTLV-1) infects and transforms CD4+ T-lymphocytes both in vivo and in vitro. Although the Tax protein of HTLV-1 has been strongly implicated as a transforming agent, other virally encoded proteins may also play a role in the transformation process. In addition to the rex and tax genes, the pX region of the HTLV-1 genome contains two open reading frames (pX-I and pX-II) which encode the putative viral accessory proteins known as p12I, p30II, and p13II. Mutations in the ACH molecular clone of HTLV-1 that are predicted to abrogate the expression of p12I, p13II and p30II were constructed. These mutations had no effect on viral replication or the immortalization of primary lymphocytes. Although these proteins are dispensable for viral replication and immortalization in vitro, it remains possible that they alter infection in vivo.

Cells, Cultured↗
PubMed1996

Inhibition of HTLV-I induction and virus-induced syncytia formation by oligodeoxynucleotides.

HTLV-I is an exogenous human retrovirus that is a causative agent of adult T cell leukemia (ATL). In addition to the structural genes (gag, pol and env), a gene termed pX is postulated to be associated with leukemogenesis in ATL. Since no effective chemotherapy is currently available, it is important to find suitable therapeutic means against ATL. Here, we tested the inhibitory effect of antisense oligodeoxynucleotides (ODNs) on HTLV-I infection in different systems. ODNs were synthesized with the phosphorothioate backbone targeted to either structural genes or transactivator genes. The phosphorothioate ODNs were found to have two distinct target sites to exert their effect on HTLV-I infection: 1) Several ODNs, including sense ODNs and random oligomers, blocked syncytium formation induced by HTLV-I at a concentration of 0.1 microM. Their inhibitory effect on syncytium formation seemed to be exerted in a nonantisense manner, most probably due to their interaction with the cell membrane. 2) Efficient suppression by ODNs of gag gene expression after chemical induction was observed in HTLV-I-transformed T cells in an antisense manner. In this suppression, tax-antisense ODN showed virtually complete inhibition of gag protein expression, but not RNA expression, at the concentration of 0.1 microM, whereas tax-sense ODN displayed a weak inhibitory effect. Our results suggest that the influence of the phosphorothioate compound should be considered from the aspect of two separated mechanisms of antiviral activity, the effects on early (viral adsorption) and late (translation) phase infection.

Animals↗