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PubMed2002

The role of the thymus in development of necrotizing arteritis in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type-I.

Necrotizing arteritis mimicking polyarteritis nodosa occurred in transgenic rats carrying the env-pX gene of human T-cell leukemia virus type I. To investigate the pathogenesis of necrotizing arteritis in these rats (env-pX rats), adoptive transfers of spleen cells and bone marrow cells were done from env-pX rats before they developed arteritis to nontransgenic rats. Necrotizing arteritis occurred in lethally irradiated nontransgenic rats reconstituted by env-pX spleen cells, thus indicating that the env-pX transgene in affected vessels may not be essential for the development of arteritis. In contrast, arteritis was not induced in nontransgenic recipients by adoptive transfers of env-pX bone marrow cells, which suggested that T cells derived from the env-pX thymus may play a role in the development of arteritis. To clarify if the process of differentiation of T cells in the env-pX thymus is crucial to develop necrotizing arteritis, reciprocal exchange of thymus frameworks was done between env-pX and nontransgenic rats. Necrotizing arteritis occurred in nontransgenic rats with an env-pX thymus framework, whereas development of arteritis was suppressed in env-pX rats in which the thymus framework was replaced with a nontransgenic one. This collective evidence shows that the thymus is directly associated with the development of necrotizing arteritis in env-pX rats.

Animals↗
PubMed1996

The association of antibodies against human T cell lymphotropic virus type I (HTLV-I) pX gene mutant products with HTLV-I-associated myelopathy/tropical spastic paraparesis.

Antibodies specific for the products of the human T cell lymphotropic virus type I (HTLV-I) pX frame-shift mutants were studied by ELISA. The serum IgG antibodies to the synthetic peptide corresponding to one nucleotide insertion at position 7784 were significantly more common in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in HTLV-I carriers who had neither HAM/TSP nor adult T cell leukemia (39% vs. 5%). The seropositivities to the other synthetic peptides, which corresponded to the one nucleotide deletion at position 7475 and the internal deletion of nt 7754-7819 and nt 7853-7936, were rare. A genetic study confirmed the presence of the responsible mutation of the pX gene in peripheral blood mononuclear cells and central nervous system tissue from HTLV-I-infected subjects with and without HAM/TSP. These results suggest that HTLV-I pX frame-shift mutants are expressed in vivo in HTLV-I carriers; they also induce antibodies. especially in those with HAM/TSP.

Adult↗
PubMed1990

Recognition of human T cell leukemia virus type I (HTLV-I) gag and pX gene products by MHC-restricted cytotoxic T lymphocytes induced in rats against syngeneic HTLV-I-infected cells.

We established rat T cell lines expressing human T cell leukemia virus type I (HTLV-I) Ag from inbred strains of rats, WKA/H, DA, and F344, to study CTL response against the HTLV-I-infected cells. HTLV-I-specific Ag expressed in these rat cells were HTLV-I gag Ag, p19, p24, and p15, and pX Ag, p40tax and p27rex, but not env Ag, as determined by immunofluorescence and immunoblot assays. By immunization of rats with syngeneic HTLV-I-infected cells, CTL against syngeneic HTLV-I-infected cells and antibodies to HTLV-I Ag were generated in WKA/H and DA rats. The bulk CTL cultures from WKA/H and DA rats lysed specifically syngeneic SV40-transformed kidney cells infected with recombinant vaccinia viruses (RVV) expressing HTLV-I gag and pX Ag, but not those infected with RVV expressing HTLV-I env Ag or a control vaccinia virus. From WKA/H rat CTL cultures, four CTL clones reactive with syngeneic HTLV-I-infected cells were isolated, three of which were specific for p27rex/p21x, but the Ag recognized by the other CTL clone was not defined with any RVV used. These results indicate that HTLV-I gag and pX gene products are recognized by MHC-restricted rat CTL specific for syngeneic HTLV-I-infected cells.

Animals↗
PubMed1996

[Case of adult T-cell leukemia without antibodies for HTLV-I but with for pX gene region].

A 76-year-old woman had lymphocytosis with lymphocytes having convoluted or lobulated nuclei. These abnormal lymphocytes (leukemic cells) were positive for CD4, and some expressed IL-2R (CD25) and CD3 molecules, respectively. These morphologic and phenotypic features were compatible with adult T-cell leukemia, but serum antibodies to human T-cell lymphotropic virus type I (HTLV-I) were not detected by the particle aggregation method and an enzyme-linked immunosorbent assay. The polymerase chain reaction showed that the LTR, gag, pol, and env regions of HTLV-I proviral DNA had not been incorporated into the leukemic cells. Only the pX region was detected in these leukemic cells.

Aged↗
PubMed2001

[The effect of estrogen receptor gene Px haplotype on bone mineral density in Chinese postmenopausal women].

OBJECTIVE: To investigate the relationship among the PvuII and XbaI polymorphism of estrogen receptor (ER) gene and bone mineral density (BMD, z-score) and bone biochemical markers in Chinese postmenopausal women. METHODS: The BMD of lumbar vertebrae (L2-4) and femoral neck (FN) of 186 postmenopausal women (aged 65.0 +/- 0.6 yr) were measured by DEXA. The polymorphism of ER gene (PvuII and XbaI) was detected by PCR-RFLP method. Serum AKP, BGP and urinary Pyd were measured by ELISA. Results The polymorphism of ER receptor can be divided into two sets: PP (14.5%), Pp (50.0%), and pp (35.5%); and 3 PvulI RFLPs and XX (7.0% ), Xx (27.4%), and xx (65.6%) 3 XbaI RFLPs. The bone markers were not significantly different among the 3 groups in each of the two sets of polymorphism. The FN BMD of women of pp genotype was higher than that of Pp genotype (P = 0.02). The BMD of 12-4 was higher in women of XX genotype than those in women of Xx and xx genotypes (P = 0.0003 and 0.0002 respectively). Women without Px haplotype (PPXX, PpXX, ppxx, n=79) had higher L2-4 BMD (P = 0.02) and FN BMD (P = 0.03) and lower serum AKP (P = 0.04) than those with Px genotype (PPxx and PPXx, Ppxx, PpXx, n=107). CONCLUSION: pp and XX genotype of ER gene may play a certain role in maintaining FN and L2-4 BMD. The genotypes without Px haplotype might exert some favorable effect on BMD, while those with Px haplotype may be harmful to bone

Aged↗
PubMed1986

A sequence homology between the pX genes of HTLV-I/II and the murine IL-3 gene.

Searching the protein sequence database for amino acid sequences homologous to the x-lor sequence in the pX region of human T-cell leukemia virus types I and II (HTLV-I/II), we found that there is a region of 38 amino acids where the murine interleukin 3 (IL-3) sequence has a 40% homology with the x-lor sequence. A statistical analysis shows that this homology is highly significant with a probability of 1.57 X 10(-10). The biological implication of this homology is discussed.

Amino Acid Sequence↗
PubMed1998

Promotion of early osteoclastogenesis and B lymphopoiesis in the bone marrow of transgenic rats with the env-pX gene of human T-cell lymphotropic virus type I.

Human T-cell lymphotropic virus type I (HTLV-I) is associated with various clinical disorders including adult T cell leukemia, myelopathy, arthropathy. Hypercalcemia resulting from osteoclast activation and a variety of hematopoietic abnormalities have been also observed in HTLV-I infected patients, however, precise mechanism about initial trigger(s) prior to presenting symptoms is still unknown. In this study, to assess effects of HTLV-I on hematopoiesis, we analysed characteristics of early hematopoietic precursors in HTLV-I env-pX transgenic rats. Progenitor cells for osteoclasts were significantly increased even in the marrow of asymptomatic env-pX rats. Progenitors for B cells were also highly enriched, while colony forming cells (CFC) elicited by GM-CSF(CFU-GM) and M-CSF(CFU-M) were comparable to normal littermates. Following arthritis in env-pX transgenic rats, osteoclastogenesis was further augmented and the CFCs were increased. Bone marrow cells carrying adjuvant-induced arthritis retained a constant number of progenitors for osteoclast and B lymphocytes, whereas the number of CFU-GM and CFU-M increased. These results indicate that the env-pX transgene affect early stages of osteoclast and B-cell lineages prior to developing diseases, in contrast, an increase of the CFCs was caused indirectly by arthritis. This study provides a novel standpoint for the mechanisms of pathogenesis by HTLV-I.

Animals↗
PubMed1991

Predominant recognition of human T cell leukemia virus type I (HTLV-I) pX gene products by human CD8+ cytotoxic T cells directed against HTLV-I-infected cells.

We established long-term cell lines of cytotoxic T lymphocytes (CTL) specific for human T cell leukemia virus type I (HTLV-I) from peripheral blood lymphocytes (PBL) of a patient with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), an HTLV-I-carrier with Sjögren syndrome, and an asymptomatic HTLV-I-carrier, by repeated stimulation with autologous HTLV-I-infected T cells in vitro. CTL derived from the patient with HAM/TSP expressed CD8 antigen, and their function was restricted by HLA-A2. They showed cytotoxic effects predominantly against the target cells expressing HTLV-I p40tax among the autologous B cell lines infected with vaccinia recombinants containing various HTLV-I genes which served as targets. These data are consistent with the previously reported findings that fresh PBL of HAM/TSP patients contain p40tax-specific CTL activity. Furthermore, CTL derived from the patient with Sjögren syndrome without neurological involvement also demonstrated cytotoxicity predominantly to p40tax. The cytotoxicity to the target cells experimentally expressing p40tax was blocked by unlabeled HTLV-I-infected cells possessing HLA-A2. HTLV-I-specific cytotoxicity was also inhibited by unlabeled B cells bearing p40tax. Thus, HTLV-I p40tax-specific cytotoxicity is mediated by the major CTL population activated by native HTLV-I antigens in patients with HAM/TSP or Sjögren syndrome. In contrast to the CTL of these patients, CTL similarly induced from the asymptomatic HTLV-I-carrier, which were highly cytotoxic to autologous HTLV-I-infected T cells, did not show significant levels of cytotoxicity to autologous B cells expressing p40tax.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Molecular analysis of a HTLV-IpX defective human adult T-cell leukemia.

Fresh and cultured leukemia cells from an adult T-cell leukemia (ATL) patient which possessed gag and env gene defective human T-cell leukemia virus type I (HTLV-I) provirus genome were molecularly analyzed. Cells from both fresh and the established cell line, named KB-1 showed identical surface markers of helper T cells, expressed the interleukin 2 (IL-2) receptor and had an identical defective HTLV-I provirus genome with deletions of the gag and env genes involving pX gene exon 2. The KB-1 cells grew vigorously in vitro, even in the absence of IL-2 and the culture supernatant of KB-1 contained a large amount of IL-2. Neither pX mRNA nor p40(TAX) protein was detected in the KB-1 cells. The collective evidence suggests that the pX gene was not functioning in this particular ATL case. The biological function of the HTLV-I genes, especially the pX gene is discussed in relation to the early and late leukemogenesis of ATL.

Blotting, Southern↗
PubMed1995

Human T-cell lymphotropic virus type I in Iranian-born Mashhadi Jews: genetic and phylogenetic evidence for common source of infection.

High prevalence of human T-cell lymphotropic virus type I (HTLV-I) infection and disease has been identified among Iranian-born Mashhadi Jews, an ethnically segregated, highly inbred population. To determine the origin and genetic diversity of HTLV-I in this group, 1,039 bp spanning selected regions of the HTLV-I gag, pol, env and pX genes were enzymatically amplified and sequenced directly from DNA of five Mashhadi Jews (three with spastic myelopathy and two asymptomatic carriers). Alignment and comparison of these sequences with cosmopolitan and Australo-Melanesian topotypes of HTLV-I indicated that the HTLV-I strains from Mashhadi Jews, which were > or = 99.9% identical among themselves, exhibited considerable sequence similarity (> or = 99%) to HTLV-I strains from southern India, suggesting a common source of infection. Phylogenetic analysis, using the maximum parsimony method, was consistent with a single-source introduction of HTLV-I into the Mashhadi Jewish community.

Adult↗
PubMedDate not supplied

Genetic and phylogenetic analyses of human T-cell lymphotropic virus type I variants from Melanesians with and without spastic myelopathy.

Molecular variants of human T-cell lymphotropic virus type I (HTLV-I) have been isolated recently from lifelong residents of remote Melanesian populations, including a Solomon Islander with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) or HTLV-I myeloneuropathy. To clarify the genetic heterogeneity and molecular epidemiology of disease-associated strains of HTLV-I, we enzymatically amplified, then directly sequenced representative regions of the gag, pol, env, and pX genes of HTLV-I strains from Melanesians with and without TSP/HAM, and aligned and compared these sequences with those of HTLV-I strains from patients with TSP/HAM or adult T-cell leukemia/lymphoma and from asymptomatic carriers from widely separated and culturally disparate populations. Overall, the HTLV-I variant from the Solomon Islander with TSP/HAM, like HTLV-I strains from asymptomatically infected Melanesians, diverged by approx 7% from cosmopolitan HTLV-I strain. No disease-specific viral sequences were found. Gene phylogenies, as determined by the unweighted pair-group method of assortment and by the maximum parsimony method, indicated that the Melanesian and cosmopolitan strains of HTLV-I have evolved along separate geographically dependent lineages, one comprised of HTLV-I strains from Papua New Guinea and the Solomon Islands, and the other composed of virus strains from Japan, India, the Caribbean, Polynesia, the Americas, and Africa. The total absence of nonhuman primates in Papua New Guinea and the Solomon Islands precludes any possibility that the Melanesian HTLV-I strains have evolved recently from the simian homolog of HTLV-I.

Adult↗
PubMed1991

In vivo genomic variability of human T-cell leukemia virus type I depends more upon geography than upon pathologies.

To investigate the geography- and disease-associated genomic variation of human T-cell leukemia virus type I (HTLV-I), we studied ex vivo DNA from peripheral blood lymphocytes from nine patients by polymerase chain reaction and direct DNA sequencing. For each viral strain, 1,917 bp was sequenced, including parts of the long terminal repeat, the env gene, and the px II, px III, and px IV coding frames of the px region. The number of genomic variations observed in the U3 region of the long terminal repeat was higher than that seen in the env and px genes. Very few mutations were present in the px II and px III genes. In contrast, the px IV open reading frame exhibited numerous single point mutations. While no specific mutation could be linked to any pathology (adult T-cell leukemia/lymphoma or tropical spastic paraparesis/HTLV-I-associated myelopathy), variations among HTLV-I isolates from different geographic areas (Ivory Coast, Caribbean, and Japan) existed. The Ivory Coast HTLV-I appeared to represent a group by itself.

Base Sequence↗
PubMed1994

[Pathological and molecular analyses of mammary tumors induced in HTLV-I pX transgenic rats].

The pX gene of human T-cell leukemia virus type I (HTLV-I) is known to be a potent transactivator of the viral gene and the host genes which are important for cell proliferation in vitro. It has been reported that various diseases occur in transgenic mice harboring either tax, pX, or env-pX gene, such as mesenchymal tumor, neurofibroma, thymic atrophy, muscle degeneration, exocrinopathy and arthropathy. We previously demonstrated that rat but not mouse CD4 positive T cells could be easily infected and immortalized by HTLV-I and infectious transmission of HTLV-I induced HAM/TSP-like myelopathy in WKAH rats after long incubation periods of 16 months. These observations prompted us to produce a series of transgenic rats that expressed the pX gene products under the control of mouse H-2Kd promotor in order to evaluate further the biological and pathological function of the pX gene in vivo. In various tissues of pX transgenic rats (pX rats), pX mRNA was constitutively expressed irrespective of age. PX rats developed mammary tumors with massive infiltration by neutrophils as early as 9 months of age. Pathological and immunohistochemical examination revealed that the tumors were undifferentiated carcinomas of the mammary gland origin. They were transplantable into pX rats, but not into normal syngenic rats. High levels of mRNA expression of not only the pX transgene but also the host genes such as Gro (melanoma growth-stimulatory activity/KC), MIP-2 (macrophage inflammatory protein-2) and IL-1 alpha were demonstrated in the tumor tissues. Gro and MIP-2 which were known as IL-8 families were likely to be produced by tumor cells and appeared to be responsible for neutrophil infiltration in the tumor tissues. Lastly, pX rats described here appear to be suitable animal models for elucidating mechanisms involved in the tumorigenesis and the transactivation of the cellular genes by HTLV-I, especially by the pX gene products in vivo.

Animals↗
PubMed1984

Nakahara memorial lecture. Human T-cell leukemia virus type I: molecular biology and its implications in adult T-cell leukemia.

Isolation and characterization of the human T-cell leukemia virus (HTLV) type I was carried out from patients with adult T-cell leukemia (ATL). Total nucleotide sequence of the provirus genome was determined and the HTLV was distinguished from other retroviruses by a unique gene pX and also by its extremely long R sequence in the long terminal repeat (LTR). HTLV was demonstrated to be a causative agent of ATL by monoclonal integration of the proviruses in ATL cells. However, nonspecific provirus integration in ATL cells disproved the direct insertional activation of a specific cellular onc gene, eventually suggesting that a transacting viral function was involved in the leukemogenesis. A gene product of the unique gene pX and trans-activation of the transcription by the product was identified. This pX gene function might explain the leukemogenesis in ATL. The mass-production of the env gene products and their identified function provided information useful for developing the systems for diagnosis and prevention of HTLV infection and ATL.

DNA, Viral↗
PubMed1994

Sequence heterogeneity of HTLV-I proviral DNA in the central nervous system of patients with HTLV-I-associated myelopathy.

The nucleotide sequence of human T-lymphotropic virus type I (HTLV-I) in central nervous system tissue was determined in 3 autopsy cases with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 1 seropositive carrier without HAM/TSP but with multiple sclerosis. All HAM/TSP samples (3 spinal cords and 2 brains) and the sample from the seropositive carrier without HAM/TSP (brain) were positive for HTLV-I env (5146-6681), pX5' (6549-7494), and pX3' (7354-8276) regions by the two-step polymerase chain reaction method. A nucleotide sequence analysis of the pX5' and pX3' polymerase chain reaction products from nucleotides 6631 to 8259 revealed heterogeneity of the HTLV-I genome in all cases. It is notable that 13 of 50 clones derived from the pX3' polymerase chain reaction products were defective in the tax open reading frame while 7 were defective in the rex open reading frame in the HAM/TSP samples. All 17 clones from 1 HAM/TSP case were defective in the pX open reading frame II. One nucleotide insertion at 7784 creating a frame shift in both tax and rex was seen in all 3 HAM/TSP cases but not in the HTLV-I carrier without HAM/TSP. The pX-defective mutants found frequently in the central nervous system may 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.

Aged↗