Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Melanoma tumor antigens, MAGE-1 and -3 are presented on HLA-A1 and -Cw*1601, or -A1 and -A2, respectively, to the corresponding cytotoxic T lymphocytes (CTL). If CTL recognizing these antigens were generated in patients, clones of positive tumor cells should be eliminated. To ascertain whether such an immunological response is active in patients with lung cancer and to determine what fraction of lung cancer patients are candidates for MAGE oriented immunotherapy, we assessed the relationship between HLA-A1 or -A2 expression and MAGE-1 or -3 gene expression in their tumors. MAGE-1 and -3 were detected in 18/55 (33%) and 23/55 (42%), respectively, by reverse transcriptase (RT)-polymerase chain reaction (PCR). Allele specific PCR revealed HLA-A1 and -A2 alleles to be expressed in 0/55 (0%) and 22/55 (40%) of our cohort, respectively. Among the 22 patients with HLA-A2 genotype, expression of HLA class I antigens detectable by immunohistochemistry was lost in five (23%) cases. The frequency of MAGE-3 expression in HLA-A2 patients was 5/17 (29%), somewhat lower than that of patients without HLA-A2 expression, 18/38 (47%), although the difference was not statistically significant (P = 0.17). Neither was there a significant association between HLA-A2/MAGE-3 co-expression and survival (P = 0.15, logrank test). We conclude that there is no clear evidence for elimination of lung cancers co-expressing HLA-A2 and MAGE-3 in vivo. Approximately 10% (5/55) of Japanese lung cancer patients are potential candidates for MAGE-3-based immunotherapy.
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PMID:Frequency of MAGE-3 gene expression in HLA-A2 positive patients with non-small cell lung cancer. 971 30

Unlike other somatic cells, human placental trophoblast cells do not express the highly polymorphic HLA-A and HLA-B human leukocyte major histocompatibility antigens that would stimulate maternal immunological rejection of the fetus. To investigate mechanisms underlying cell lineage-specific expression, cell lines were generated from homozygous matings of HLA-B27 transgenic mice. Trophoblast cell lines were generated from gestation day 10 placentas and fibroblasts were cultured from gestation day 13/14 embryos. Polymerase chain reaction (PCR) readily identified HLA-B DNA in transgenic trophoblastic cells but specific mRNA was of low abundance, being detectable by reverse transcriptase PCR but not by Northern blot hybridization. HLA-B-specific protein in/on the trophoblast cells was undetectable by cell enzyme-linked immunosorbent assay and the protein was not induced by exposing the trophoblastic cells to interferon-gamma (IFN-gamma). Restricted expression was specific for the HLA-B transgene and its antigen; IFN-gamma-inducible endogenous H-2Db class I antigens were detectable on the trophoblast cells. In contrast to the trophoblastic cells, HLA-B27 transgenic fibroblasts expressed IFN-gamma-inducible HLA class I antigens as well as H-2Db antigens. Thus, the mechanism(s) regulating expression of the polymorphic HLA-B antigen in trophoblastic cells is gene-specific, IFN-gamma-resistant and operative at the level of transcription or immediate post-transcription.
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PMID:Differential expression and regulation of a human transgene, HLA-B27, in mouse placental and embryonic cell lines. 973 41

Expression of HLA class I molecules is essential for the recognition of tumor cells by CD8+ T cells. In this study, 48 bioptic samples of 42 patients in all stages of melanoma were investigated after short-time cultivation of tumor cells. To confirm melanocytic origin of cultured cells, samples were screened for mRNA expression of melanoma markers gp100, tyrosinase, MAGE-3, MelanA, and MUC18 by reverse transcriptase-polymerase chain reaction. Surface expression of specific HLA-A and -B allospecificities on melanoma cells were analyzed with a standard microcytotoxicity assay after stimulation with interferon (IFN)-alpha and compared with the background found in peripheral blood mononuclear cells from the corresponding patients. Immunohistochemistry and flow cytometry confirmed specific losses in cases where the appropriate monoclonal antibodies were available. The level of expression of HLA-I, HLA-II, and intercellular adhesion molecule 1 antigens on melanoma cells cultured in the presence or absence of IFN-alpha and IFN-gamma was determined cytofluorometrically. All cell cultures tested were found to be positive for one or more melanocytic markers by reverse transcriptase-polymerase chain reaction. The specific HLA-I alleles on the cultured cells were detectable in 45 of 48 samples. In 11 cases a specific loss of one HLA-I allele was observed (2 x A2, B7, B8, B18, 4XB44, B47, B49). Ten of these samples were derived from locoregional lymphnode metastases or from distant metastatic tumors. Only one sample from a primary melanoma showed a specific loss of HLA-I (B47). IFN-alpha upregulated expression of HLA-I up to 4-fold. IFN-gamma enhanced the appearance of HLA-II up to 35-fold and the expression of intercellular adhesion molecule 1 up to 40-fold. Selective loss of HLA-I allospecificities might be a major step in tumor progression.
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PMID:Higher frequency of selective losses of HLA-A and -B allospecificities in metastasis than in primary melanoma lesions. 974 Feb 47

The immunogenic potential of melanoma cells and their recognition by the host's cytotoxic cells depends on the presence and on the level of expression of human leukocyte antigen (HLA) class I antigens, costimulatory molecules and melanoma-associated antigens (MAA), on neoplastic cells. In this study, we demonstrate that the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR), significantly (p < 0.05) enhanced the constitutive expression of HLA class I antigens, HLA-A1 and -A2 alleles, and of the costimulatory molecules intercellular adhesion molecule-1 and lymphocyte function-associated antigen-3, on a panel of 12 melanoma cells. This upregulation peaked at day 4, slowly decreased thereafter, and returned to baseline levels 32 days after the end of treatment. In addition, treatment with 5-AZA-CdR induced a persistent expression of MAGE-1 in Mel 275 melanoma cells; this was still detectable, by reverse transcriptase polymerase chain reaction, 60 days after the end of treatment. In contrast, 5-AZA-CdR did not affect the constitutive expression of the high molecular weight-MAA by the melanoma cells investigated. These observations, together with data obtained comparing the effect of 5-AZA-CdR with that of interferon-gamma, strongly suggest that 5-AZA-CdR may have prospective therapeutic implications in active and/or passive specific immunotherapy for human melanoma.
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PMID:Prolonged upregulation of the expression of HLA class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2'-deoxycytidine (5-AZA-CdR). 992 95

Peptide/MHC tetrameric complexes were used to enumerate the frequency of HLA class I-restricted epitope-specific CD8+ T cells in 18 HLA-A*0201 HIV type 1-infected asymptomatic patients. HLA-A*0201 molecules were complexed to HIV Gag p17 (amino acids 77-85) and reverse transcriptase (amino acids 464-472) peptides, biotinylated, and bound to streptavidin-phycoerythrin to form tetramers. We show in this study that 17 of 18 HIV-1-infected asymptomatic patients have circulating frequencies of 1/50-1/1000 CD8+ T cells that recognize both Gag and Pol CTL epitopes or either epitope alone. The functional nature of these cells is open to interpretation, as we show that despite relatively high frequencies of fresh epitope-specific CD8+ T cells, variant epitope sequences in viral plasma progeny were rare. In addition, the majority of tetramer-positive cells did not display discernible fresh CTL activity; only after restimulation with specific peptide in culture was there an expansion of epitope-specific CD8+ cells, correlating with high CTL activity. These data suggest that fresh tetramer-stained cells probably represent memory precursors; we demonstrate, with the application of highly active antiretroviral therapy, that the interruption of chronic antigenic stimulation causes significant reductions in the frequency of these cells in five of six patients. In conclusion, this study provides evidence that persistently replicating viral populations are probably required to maintain high frequencies of HIV-1 epitope-specific CD8+ T cells in asymptomatic chronically infected individuals
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PMID:Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART). 997 42

The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-cell responses. We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-gamma) production by CD8(+) T cells. In some patients, particularly those initiating three-drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of anti-HIV-1 CD8(+) T cells that correlated with decreases in HIV-1 RNA and increases in T-cell counts. In the other patients, HIV-1-specific T-cell functions either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HIV-1 RNA. These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8(+) T cells specific for the cytomegalovirus pp65 matrix protein. The level and breadth of CD8(+) cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN-gamma production and HLA tetramer staining after combination therapy, were related to the corresponding responses prior to treatment. There was, however, a stable, residual population of potentially immunocompetent HIV-1-specific T cells remaining after therapy, as shown by tetramer staining of CD8(+) CD45RO(+) cells. These results indicate that new strategies will be needed to target residual, immunocompetent HIV-1-specific CD8(+) T cells to enhance the effectiveness of antiretroviral therapy in patients with advanced immunodeficiency.
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PMID:Anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-lymphocyte reactivity during combination antiretroviral therapy in HIV-1-infected patients with advanced immunodeficiency. 1075 25

The origins of virus evolution may be traced to Archeabacteria since Inouye and Inouye (6) discovered a retroelement with a gene for reverse transcriptase in the bacterial genome and in the satellite, multiple copy single stranded DNA (msDNA) in the soil bacterium Myxococcus xanthus. It was possible (8) to define the evolution of retroelements in eukaryotic cells of plants, insects (gypsy retrovirus) and vertebrates. The replication of RNA viruses in eukaryotic cells allowed for the viral RNA genome to integrate a cellular ubiquitin mRNA, as reported for BVDV (24). Another example is the integration of 28S ribosomal RNA into the hemagglutinin gene of an influenza virus. This change in the hemagglutinin gene led to an increased pathogenicity of the influenza virus (25). In contrast to RNA viruses, DNA viruses had evolved by inserting cDNA molecules derived from mRNA transcripts of cellular genes or foreign viral RNA. It is of interest that the virus acquired cellular genes in the genomes of DNA viruses represent genes that code for proteins that inhibit cellular molecular processes related to HLA class I and II molecules. The other acquired genes are cellular genes that code for cytokines that are capable of inhibiting antigen presentation to T cells by antigen presenting cells (APC) by dendritic Langerhans cells. The acquisition of cellular genes by DNA viruses enhances their pathogenicity by inhibiting the hosts' defense systems.
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PMID:Evolution of viruses by acquisition of cellular RNA or DNA nucleotide sequences and genes: an introduction. 1102 85

A new HLA class I null allele has been identified within the B44 group by combined serological and molecular typing of a blood donor. Based on full-length cDNA sequencing, this novel HLA-B*4419N allele was found to differ from B*4402 by one single base pair deletion at position 7 of exon 1 which results in a stop at codon 19. This mutation was confirmed by polymerace chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) hybridization on genomic DNA. Based on family typing, this new allele segregates with the haplotype A*01-B*4419N-Cw*0501-DRB1*1301-DRB3*0101. Since nonsense codons are generally associated with increased mRNA decay, we investigated B*4419N mRNA by semi-quantitative reverse transcriptase (RT)-PCR and by cDNA cloning efficiency. Comparison of B*4419N cDNA to B*4402 control cDNA and to B35 cDNA levels in the same donor, as well as the analysis of cloned inserts, revealed that the exon 1 mutation did not significantly influence B*4419N steady-state mRNA.
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PMID:Sequence of a new class I null allele within the HLA-B44 specificity. 1114 92

Several mechanisms of immune escape might be in operation in Epstein-Barr virus (EBV)-associated nasal NK/T-cell lymphoma. We have previously shown the downregulation of the immunogenic EBV nuclear antigens by alternative promoter usage and the preferential selection of the deletion genotype of latent membrane protein 1 in nasal lymphoma. To understand further the strategies used for immune escape by this tumor, we examined by immunohistochemistry HLA class I expression in 15 cases using frozen sections, along with beta(2)-microglobulin and transporter associated with antigen processing 1 (TAP1) expression in 39 cases using paraffin sections. All nasal NK/T-cell lymphomas showed positive staining for HLA class I, beta(2)-microglobulin and TAP1 on most tumor cells, except for two cases (5%) in which most of the tumor cells lacked beta(2)-microglobulin staining. We next immunostained for interleukin-10 on frozen sections in 13 cases, all of which showed strong expression by most tumor cells. Transcription of human interleukin-10 but not EBV BCRF1 (viral interleukin-10) was identified by reverse transcriptase-polymerase chain reaction in these nasal NK/T-cell lymphomas. Overall, our data suggest that global downregulation of HLA class I or TAP1 rarely accounts for the ability of nasal NK/T-cell lymphoma to evade immunosurveillance and that other immune escape mechanisms may be operating in nasal NK/T-cell lymphoma, such as production of interleukin-10 to suppress the local immune response.
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PMID:Expression of HLA class I, beta(2)-microglobulin, TAP1 and IL-10 in Epstein-Barr virus-associated nasal NK/T-cell lymphoma: Implications for tumor immune escape mechanism. 1134 May 74

The presentation of endogenously synthesized peptides in association with HLA class I molecules allows the activation of CD8(+) lymphocytes. Tumor cells often fail to present antigenic peptides resulting in the immune escape of metastasizing cells. The aim of this study was to elucidate possible molecular mechanisms leading to reduced antigen presentation in melanoma. Melanoma cell short-time cultures were genotypically and phenotypically HLA-typed by sequence-specific primer polymerase chain reaction and complement-mediated microlymphocytotoxicity assays, respectively. Flow cytometric analysis of HLA-A2 and HLA-A3 allospecificities were performed to confirm typing results. Transcriptional levels of classical HLA-A, HLA-B genes and nonclassical HLA-G genes were detected using quantitative real-time reverse transcriptase polymerase chain reaction (LightCycler). We found loss or downregulation of HLA proteins in 18% (for HLA-A) and 53% (for HLA-B) of all tested metastases. Genomic analysis, however, revealed the presence of the corresponding HLA class I gene in six out of seven cases. On the level of gene transcription we observed a differential regulation of HLA-A, HLA-B, and HLA-G mRNA expression. There was no correlation between classical and nonclassical HLA gene transcription, but the transcriptional levels of classical HLA corresponded to the protein expression levels. Furthermore, an overall reduced amount of HLA class I gene transcription was observed in melanoma metastases during disease progression in three individuals. We postulate that there is a transcriptional regulation of HLA class I gene expression in melanoma cells. These data suggest that treatment approaches aimed at activating specific cytotoxic T lymphocytes are most successful in early disease.
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PMID:Decreased intraindividual HLA class I expression is due to reduced transcription in advanced melanoma and does not correlate with HLA-G expression. 1188 14


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