Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retrovirus particles with type C morphology were found in two T-cell lymphoblastoid cell lines, HUT 102 and CTCL-3, and in fresh peripheral blood lymphocytes obtained from a patient with a cutaneous T-cell lymphoma (mycosis fungoides). The cell lines continuously produce these viruses, which are collectively referred to as HTLV, strain CR(HTLV(CR)). Originally, the production of virus from HUT 102 cells required induction with 5-iodo-2'-deoxyuridine, but the cell line became a constitutive producer of virus at its 56th passage. Cell line CTCL-3 has been a constitutive producer of virus from its second passage in culture. Both mature and immature extracellular virus particles were seen in thin-section electron micrographs of fixed, pelleted cellular material; on occasion, typical type C budding virus particles were seen. No form of intracellular virus particle has been seen. Mature particles were 100-110 nm in diameter, consisted of an electron-dense core surrounded by an outer membrane separated by an electron-lucent region, banded at a density of 1.16 g/ml on a continuous 25-65% sucrose gradient, and contained 70S RNA and a DNA polymerase activity typical of viral reverse transcriptase (RT; RNA-dependent DNA nucleotidyltransferase). Under certain conditions of assay, HTLV(CR) RT showed cation preference for Mg(2+) over Mn(2+), distinct from the characteristics of cellular DNA polymerases purified from human lymphocytes and the RT from most type C viruses. Antibodies to cellular DNA polymerase gamma and anti-bodies against RT purified from several animal retroviruses failed to detectably interact with HTLV(CR) RT under conditions that were positive for the respective homologous DNA polymerase, demonstrating a lack of close relationship of HTLV(CR) RT to cellular DNA polymerases gamma or RT of these viruses. Six major proteins, with sizes of approximately 10,000, 13,000, 19,000, 24,000, 42,000, and 52,000 daltons, were apparent when doubly banded, disrupted HTLV(CR) particles were chromatographed on a NaDodSO(4)/polyacrylamide gel. The number of these particle-associated proteins is consistent with the expected proteins of a retrovirus, but the sizes of some are distinct from those of most known retroviruses of the primate subgroups.
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PMID:Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. 626 Dec 56

HTLV strain CR (HTLVCR) is a retrovirus which was isolated from a human T-cell lymphoma cell line. A protein of molecular weight 24,000 p24, was purified from this virus. Several results indicate that this p24 is an internal core protein of HTLVCR. (i) The p24 copurified with viral cores. (ii) It was labeled with 125I after disruption of the virus, but not when undisrupted virus was iodinated. (iii) The amount of p24 was directly proportional to the amount of HTLVCR. (iv) In chromatographic properties, the HTLVCR p24 behaved similarly to the major structural protein (24,000- to 30,000-molecular-weight protein) of other retroviruses. A rabbit antiserum raised against disrupted HTLVCR precipitated the labeled p24, and the precipitation was competed for by unlabeled HTLVCR and by cytoplasmic proteins from cells producing HTLVCR, but not by proteins from normal human cells, including normal growing human T-cells, and several cultured human cutaneous T-cell lymphoma lines. Proteins from several mammalian type B, type C, and type D viruses also failed to compete in this precipitation. Moreover, HTLVCR did not react in homologous and interspecies assays for p30 antigens of several mammalian type C and type D viruses. These observations agree with immunological comparisons between reverse transcriptase of HTLVCR and other retroviruses and nucleic acid sequence homology studies which indicate that the various HTLVCR isolates represent new retroviruses found in some human T-cell neoplasias.
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PMID:Immunological properties of a type C retrovirus isolated from cultured human T-lymphoma cells and comparison to other mammalian retroviruses. 626 63

A human type C retrovirus [human T-cell leukemia (lymphoma) virus; HTLV], recently isolated from young adult patients with cutaneous T-cell lymphoma or leukemia, was not detectably related to other known animal retroviruses in molecular hybridization studies, by comparison of reverse transcriptase and the major core protein p24. The p24 core protein was purified to homogeneity. The amino acid composition, the COOH-terminal amino acid, and the NH(2)-terminal amino acid sequence of the first 25 residues of this major internal structural protein were determined. These results were then compared to the known structure of the internal core protein of other retroviruses. The compositional data reveal that HTLV p24 is chemically distinct from p30-p24 of other animal retroviruses, in agreement with the earlier immunological analyses. However, HTLV p24 shares the common NH(2)-terminal proline and COOH-terminal leucine of all mammalian type C viral p30s. In addition, like bovine leukemia virus (BLV), HTLV lacks the common prolylleucylarginine tripeptide and the larger conserved region found near the NH(2) terminus of the other mammalian type C viral p30s. Alignment of the amino acid sequence of HTLV p24 with previously determined sequences of other retrovirus proteins, including BLV p24, reveals statistically significant sequence homology only to BLV. The results reported here demonstrate that HTLV p24 is related to but chemically distinct from the major core protein of other retroviruses. Similarly, previous results showed that there was no immunological crossreactivity of the p24 protein and reverse transcriptase of HTLV with other retroviruses, including BLV, and no nucleic acid sequence homology. However, the present results, combined with the common size of the p24 and reverse transcriptase, suggest that HTLV may be closer to BLV than any other known retrovirus.
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PMID:Primary structure analysis of the major internal protein p24 of human type C T-cell leukemia virus. 628 Jan 75

Human T-cell leukemia-lymphoma virus (HTLV) has now been isolated from many different patients with cutaneous T-cell lymphoma and leukemia, as judged by detection of media reverse transcriptase and virus particles and of antigenic determinants related to those of viral structural proteins p24 and p19. Molecular hybridization experiments with HTLV cDNA to viral mRNA or proviral DNA to ascertain the relatedness of four of these new isolates to the first HTLV isolate have been used. By these assays, three appear virtually indistinguishable from the original isolate, HTLV-I(CR), the second U.S. isolate (HTLV-I[MB]), and the Japanese ATLV isolates. Proviral sequences indistinguishable from those of HTLV-I(CR) were also detected in uncultured leukemic blood leukocytes from a patient of Japanese origin with adult T-cell leukemia. These viral isolates thus form a closely related virus group, HTLV-I. In contrast, however, RNA and DNA from one cell line derived from a patient with a T-cell variant of hairy cell leukemia, which expresses media reverse transcriptase and antigenic determinants related to but distinguishable from HTLV p24, did not hybridize substantially with HTLV cDNA. This latter virus appears to represent a second type of HTLV (HTLV-II), related to but substantially different from HTLV-I.
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PMID:Relatedness by nucleic acid hybridization of new isolates of human T-cell leukemia-lymphoma virus (HTLV) and demonstration of provirus in uncultured leukemic blood cells. 660 15

Glutathione depletion may play a pivotal role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection. Since certain compounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potencies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunctional inducers tested elevated the levels of glutathione and quinone reductase, a marker for phase II enzyme induction. However, only oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at inhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 microM). The antiviral effect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of anti-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibitor of HIV-1 reverse transcriptase in the template-primer binding domain. Oltipraz has been used to treat schistosomiasis in humans and is undergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (and other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1-infected individuals, not only because of their antiretroviral activity, but also by preventing the development of HIV-1-associated neoplasms.
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PMID:Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. 768 14

Mycosis fungoides (MF) is a rare form of cutaneous T cell lymphoma suspected of having a viral etiology. As in adult T cell leukemia, the virus involved may be human T lymphotropic virus type 1 (HTLV-1). We cultured the peripheral blood mononuclear cells (PBMC) of 29 patients with MF HTLV-1 seronegative by enzyme-linked immunosorbent assay and Western blot. The presence of reverse transcriptase (RT) and p24 antigen was investigated in the concentrate supernatant of the culture. The DNA of all studied patients was submitted to polymerase chain reaction and Southern blot analysis using primers and probes recognizing the tax region of HTLV-1/2 and the pol region of HTLV-1. 10 of 29 patients were found positive to HTLV-1, whereas they were always negative to RT and p24. The same results were confirmed in double blind after 6 mo. Our findings suggest HTLV-1 may be involved in the etiology of MF, at least in certain cases.
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PMID:Persistence of human T cell lymphotropic virus type 1 (HTLV-1) sequences in peripheral blood mononuclear cells from patients with mycosis fungoides. 796 73

We determined T-cell cytokine profiles in the epidermis, dermis, and blood of cutaneous T-cell lymphoma to differentiate whether unique cytokine profiles were associated with mycosis fungoides (MF) versus Sezary syndrome. Punch biopsy specimens from plaque stage MF (n = 7) were compared to Sezary skin (n = 3) after undergoing rapid heat-saline separation of epidermis from dermis. Normal adult skin (n = 11), neonatal foreskin (n = 4), untreated psoriatic plaques (n = 6), and normal donor peripheral blood leukocytes (n = 3) were studied as controls. Total RNA was extracted from all skin specimens, as well as peripheral blood leukocytes from MF (n = 3) and Sezary patients (n = 7), and was converted to cDNA by reverse transcriptase. Polymerase chain reaction amplification of cDNAs using interleukin 2 (IL-2), IL-4, IL-5, IL-10, and interferon gamma-specific primers was used to differentiate Th1-type responses (IL-2+ and interferon gamma +) from Th2-type responses (IL-4+, IL-5+, and IL-10+). beta-actin specific primers were included as a positive control for mRNA integrity. All MF specimens contained mRNAs for IL-2 and interferon gamma limited to epidermis but not IL-4, IL-5, or IL-10. In contrast, Sezary skin and blood showed a cytokine mRNA pattern dominated by IL-4, IL-5, and IL-10. MF blood showed a pattern similar to normal peripheral blood T cells with mixed detection of all T-helper cell cytokine mRNAs. All psoriasis samples contained mRNAs for IL-2 and interferon gamma in both epidermis and dermis with no IL-4 or IL-10 in either compartment. These findings demonstrate that the cutaneous lesions of MF are characterized by an epidermal Th1-type cytokine profile, whereas both the blood and skin of patients with Sezary syndrome is characterized by a Th2-type profile. This work suggests that differences in cytokine production may be related to the pathophysiology and clinical presentation in cutaneous T-cell lymphoma.
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PMID:Mycosis fungoides exhibits a Th1-type cell-mediated cytokine profile whereas Sezary syndrome expresses a Th2-type profile. 749 Apr 83

DAB486IL-2 is a recombinant toxin with the cell surface-binding domain of diphtheria toxin (DT) replaced by interleukin-2 (IL-2). To correlate clinical response with expression of components of the IL-2 receptor (IL-2R), 14 patients with cutaneous T-cell lymphoma (CTCL) received five daily 90-minute infusions every 21 days. There were no complete responses, 1 partial response (PR), 2 major biologic effects (major cutaneous improvement without change in circulating neoplastic cells), 3 stable disease (SD), and 8 progressive disease (PD). Responders had easily detected expression of CD25 (Tac; alpha-chain of IL-2R) in skin, and in two responders expression of the beta chain of the IL-2 receptor (beta-IL-2R) was detectable by reverse transcriptase-polymerase chain reaction. CD25 was also detected in 8 of 11 SD or PD patients, with beta-IL-2R in 3 of 8 SD or PD patients. Two of the three responders had anti-DT antibodies before treatment. Reversible increased hepatic transaminases occurred in 13 of 14 patients during the first course, with decreased frequency in repeated courses. The maximal serum concentration after the first infusion of DAB486IL-2 varied (1,369 +/- 1,155 ng/mL [mean +/- SD]; n = 14; range, 55 to 3,999 ng/mL) with a short half-life (T1/2 beta = 0.21 +/- 0.12 h [mean +/- SD]; range, 0.099 to 0.57 h). The area under the concentration curve varied inversely with anti-DT antibody titer. We conclude that DA-B486IL-2 has valuable activity in certain patients with CTCL. Expression of the IL-2R may be necessary but is not sufficient to predict response.
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PMID:Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study. 808 Sep 84

Cytokines are believed to play an important role in the pathogenesis of cutaneous T cell lymphoma. Data regarding the local cytokine pattern in mycosis fungoides (MF) are partly conflicting. Recent studies have suggested a shift from type 1 to type 2 cytokine pattern because IL-4 and IL-5 mRNA have been more frequently detected in lesions of advanced stages. Another study has described a type 1 cytokine pattern in MF lesions. None of the previous studies of cytokine mRNA expression in MF, however, used quantitative methods, and therefore only the presence of a cytokine, but not the level of expression, could be determined. To gain better insight into the development of cytokine pattern during tumor progression we used semiquantitative reverse transcriptase-polymerase chain reaction to analyze cytokine mRNA expression in MF skin lesions at different stages. Biopsies from patients with patch (n = 11), plaque (n = 6), and tumor (n = 3) stage MF were compared with biopsies from patients with pleomorphic T cell lymphoma (n = 5), psoriasis (n = 7), atopic dermatitis (n = 5), and nonlesional skin (n = 8). MF progression was associated with significantly higher IL-10 and lower interferon-gamma mRNA expression. Moreover, the stage-dependent increase in IL-10 mRNA expression was also found in paired samples from individual patients. Unlike in pleomorphic T cell lymphoma, however, typical T helper 2 cells did not seem to be the source of increasing IL-10 in advanced MF, because stage-independent IL-4 mRNA was rarely detected, suggesting contribution of nonlymphoid cells to local IL-10 production. The overexpression of IL-10 in MF may be of importance for tumor progression, because this immunosuppressive cytokine might be involved in downregulation of immunologic tumor surveillance.
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PMID:Progression of mycosis fungoides is associated with increasing cutaneous expression of interleukin-10 mRNA. 894 70

Three clonally related lymphoma lines (Mac-1, Mac-2A and Mac-2B) derived from progressive stages of CD30+ cutaneous T-cell lymphoma were found to constitutively secrete GM-CSF. The secretion of GM-CSF was identified by the ability of cell line supernatants to stimulate growth of megakaryoblastic cell line M-07e. This supernatant-mediated stimulation was inhibited by anti-GM-CSF MoAb (>98% inhibition for Mac-1 and Mac-2B lines, and >95% for Mac-2A line). Synthesis of GM-CSF was confirmed, at the mRNA level, by reverse transcriptase PCR and, at the protein level, by ELISA. Quantification of GM-CSF in supernatants by ELISA showed that the Mac-1 line, derived from an early, clinically indolent stage of the lymphoma, produced much more GM-CSF (>1600 pg/ml) than Mac-2A and Mac-2B lines which were derived from a late, aggressive stage (30-50 and 50-120 pg/ml, respectively). Lack of inhibition of cell growth by anti-GM-CSF MoAb as well as lack of response to exogenous GM-CSF of cells cultured at low concentration have demonstrated that GM-CSF does not act directly as a growth factor for these lines. ELISA studies showed that GM-CSF concentration in serum and urine of the patient were not elevated (<5 pg/ml). From several other cell lines tested (two primary CD30+ ALCL, 2 CD30- non-lymphoblastic T-cell lymphomas and 4HD), only two HD lines with a T-lymphocyte phenotype secreted detectable amounts of GM-CSF. Our data show that cells lines from a patient with cutaneous T-cell lymphoma constitutively secrete GM-CSF, although this capacity is relatively diminished in lines developed from more advanced disease.
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PMID:Constitutive secretion of GM-CSF by three different cell lines derived from a single patient with a progressive cutaneous lymphoproliferative disorder. 916 23


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