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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus (HIV) entry is mediated not only by the CD4 receptor, but also by interaction with closely related molecules that act as membrane coreceptors. We have analyzed mRNA expression and/or cell membrane exposition of the coreceptors most widely used by diverse HIV-1 strains (CXCR4, CCR5, and CCR3) on purified hematopoietic progenitor cells (HPCs) induced in liquid suspension culture to unilineage differentiation/maturation through the erythroid (E), granulocytic (G), megakaryocytic (Mk), and monocytic (Mo) lineages. Reverse transcriptase-polymerase chain reaction (RT-PCR) and cytofluorimetric analysis showed the presence of both CXCR4 and CCR5 in quiescent HPCs, but failed to detect CCR3-specific transcripts. Chemokine expression in HPC progenies showed that CXCR4 receptor is detected on the majority of MKs from early to late stages of maturation, whereas it is moderately decreased in the Mo lineage. In the G pathway, two distinct cell populations, CXCR4(+) and CXCR4(-), were observed: morphological analysis of the sorted populations showed that the CXCR4(+) cells were largely eosinophils and the CXCR4(-) were granulocytes of the neutrophilic series. Furthermore, in the E pathway, CXCR4 was almost completely absent. CCR5 expression is restricted to Mo cultures, ie, approximately 30% to 80% cells throughout all monocytopoietic differentiation/maturation stages. Finally, CCR3 mRNA is always absent in all the unilineage cultures. Evaluation of CD4 expression by flow cytometry on both quiescent HPCs and differentiating unilineage precursors showed that the CD4 receptor is present on approximately 15% of the starting CD34(+) HPC population, highly expressed in the Mo lineage up to 80% at terminal maturation, present on 20% to 30% of maturing Mks, and not detectable in either the E or G lineage. Expression of CD4 receptor together with CXCR4 and/or CCR5 coreceptor in the four lineages correlates with hematopoietic precursor susceptibility to T-lymphotropic and macrophage (M)-tropic HIV strains infection: (1) CD4(-) G and E cells were resistant to both M-tropic and T-lymphotropic strains; (2) HPC-derived Mks were susceptible to T-tropic, but resistant to M-tropic, infection; (3) Mo differentiating cells efficiently replicate both HIV strains. Furthermore, we showed that the CXCR4 and CCR5 ligands (stromal-derived factor 1 and macrophage-inflammatory protein-1alpha [MIP-1alpha], MIP-1beta and RANTES, respectively) inhibit HIV replication in both maturing Mo and Mk cells. Taken together, our data show a lineage-specific modulation of chemokine receptor/coreceptor during hematopoietic cell differentiation and extend previous observations on the relationship between the expression of HIV receptor/coreceptors, susceptibility, and chemokine-mediated resistance to HIV infection.
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PMID:Lineage-specific expression of human immunodeficiency virus (HIV) receptor/coreceptors in differentiating hematopoietic precursors: correlation with susceptibility to T- and M-tropic HIV and chemokine-mediated HIV resistance. 1093 97

The effect of highly active antiretroviral therapy (HAART) on liver function and viral load of hepatitis C virus (HCV) was studied in 21 hemophilic men coinfected with HCV and human immunodeficiency virus (HIV). HCV RNA polymerase chain reaction was measured by branched DNA Quantiplex assay on frozen plasma samples obtained at baseline and at 24, 48, and 96 weeks after initiation of HAART. HCV RNA increased at 48 and 96 weeks after initiation of HAART therapy (198x105 Eq/mL [P=.03] and 227x105 Eq/mL [P<.0001], respectively, compared with baseline [141x105 Eq/mL]). This increase was associated with an increase in CD4 cell count and reduction in HIV viral load but no change in hepatic transaminases. With discontinuation of HAART, HCV RNA decreased as HIV RNA rebounded. Further study is required to clarify the histopathologic significance of this finding.
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PMID:Increase in hepatitis C virus load in hemophiliacs during treatment with highly active antiretroviral therapy. 1055 63

CD40 ligand (CD40L), expressed on activated T cells, binds its receptor, CD40, on dendritic cells, B cells, and monocytes/ macrophages. Human immunodeficiency virus (HIV)-infected individuals exhibit normal B-cell CD40 expression but diminished expression of CD40L on CD4 + T cells. Thus, we studied recombinant human CD40L (huCD40L) in an in vitro rhesus macaque model of acquired immunodeficiency syndrome (AIDS). huCD40L induced peripheral blood mononuclear cell (PBMC) proliferation independent of mitogenic cytokines and led to a 70% reduction in p27 production by simian immunodeficiency virus (SIV) mac239 infected PBMCs (P < 0.05). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed reduced expression of SIV gag and increased expression of interleukin (IL)-16 mRNA. Supernatants from huCD40L-stimulated PBMC and control cultures contained similar amounts of IL-16, suggesting an intracellular antiviral effect by IL-16. Phytohemagglutinin (PHA)-stimulated PBMCs similarly cultured with huCD40L showed only slight increases in chemokine production (P > 0.05). These results suggest that huCD40L inhibits replication (antigen and mRNA production) of SIVmac239. This response involves huCD40L induction of IL16 mRNA expression and appears to be independent of beta-chemokines.
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PMID:Recombinant human CD40 ligand inhibits simian immunodeficiency virus replication: a role for interleukin- 16. 1059 85

Adult T-cell leukemia (ATL) is characterized by infiltration of various tissues by circulating ATL cells, a finding often associated with a poor prognosis. Leukocyte migration from the circulation into tissues depends on integrin-mediated adhesion to the endothelium, and integrins are tightly regulated by several factors, such as chemokines. In this study, we focused on the interaction between chemokines and chemokine receptors on ATL cells to understand factors involved in ATL cell infiltration of lymphoid organs. We compared freshly isolated ATL cells from patients with and without lymphoid organ involvement for the expression of the chemokine receptor CCR7/EBI1, the functional receptor for secondary lymphoid-tissue chemokine (SLC), which is expressed at high levels by high endothelial venules of lymph nodes and Peyer's patches. Reverse transcriptase-polymerase chain reaction and flow cytometric analysis, using anti-CCR7 monoclonal antibody (CCR7.6B3), revealed that ATL cells from patients with lymphoid organ involvement expressed significantly more CCR7/EBI1 than control CD4(+)CD45RO(+) T cells and ATL cells from patients without lymphoid organ involvement. Consequently, significantly more ATL cells from patients with lymphoid organ involvement than control CD4(+)CD45RO(+) T cells and ATL cells from patients without lymphoid organ involvement adhered to surfaces coated with ICAM-1 and SLC or EBI1-ligand chemokine (ELC), another ligand for CCR7/EBI1, under static and flow conditions and migrated toward SLC or ELC at a low concentration (30 ng/ml). These findings suggest that increased CCR7/EBI1 expression plays a role in lymphoid organ infiltration of ATL cells. (Blood. 2000; 30-38)
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PMID:Increased chemokine receptor CCR7/EBI1 expression enhances the infiltration of lymphoid organs by adult T-cell leukemia cells. 1060 81

Previous studies have suggested that large quantities of bacterial lipids may accumulate and persist within host cells during chronic stages of Mycobacterium avium infections. This study intended to assess the ability of purified M. avium lipids to affect TH-1-type responses in human peripheral blood mononuclear cells (PBMC) from healthy donors. PBMC were exposed to total lipids and serovar-specific glycopeptidolipids (GPL) extracted from M. avium serovars 4 and 8, which have been reported to predominate as opportunistic infection among AIDS patients. After 24 h exposure to lipids followed by PHA/PMA treatment, IL-2 and IFN-gamma were assayed in the supernatants. Reverse transcriptase polymerase chain reaction (RT-PCR) was used for a semiquantitative estimation of mRNA for IL-2 and IFN-gamma in cell pellets at various time points. Exposure of PBMC to M. avium total lipids significantly suppressed PHA/PMA-induced secretion of IL-2 and IFN-gamma as determined by ELISA. The GPL antigens from serovar 4 were more efficient at inhibiting TH-1 responses than GPL from serovar 8. CD4(+)T-lymphocyte enrichment of PBMC demonstrated that suppression by M. avium lipids was intact without the presence of other cell populations such as monocytes and B-cells. Preliminary RT-PCR experiments showed that the secretion of TH-1 cytokines was partially affected at the transcriptional level. The results obtained showed that M. avium lipids are indeed able to modify the induction of TH-1-type cytokines by human PBMC, and suggest that accumulation of M. avium lipids in the chronic stages of infection may play an important role in the pathogenesis of HIV infection.
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PMID:Exposure of human peripheral blood mononuclear cells to total lipids and serovar-specific glycopeptidolipids from Mycobacterium avium serovars 4 and 8 results in inhibition of TH1-type responses. 1087 86

The CCR5 beta-chemokine receptor is the coreceptor for macrophage-tropic (M-tropic) strains of HIV-1 and appears to be the principal coreceptor during early stages of human immunodeficiency virus-1 (HIV-1) infection. Approximately 1%-2% of the Western European Caucasian population is homozygous for a 32-bp deletion in the coding region of the CCR5 gene, rendering them less susceptible to HIV infection. These individuals still harbor a normal immune response, thereby making CCR5 an attractive cellular target for anti-HIV therapies. Based on the natural population studies, reduction in CCR5 expression should not affect the physiologic function of the modified cells but should interfere with their susceptibility to HIV-1 infection. To downregulate this receptor, we have designed a hammerhead ribozyme (RZ) that specifically targets the CCR5 mRNA and lacks complementarity to other members of the chemokine receptor gene family. For expression of this highly specific ribozyme, we have taken advantage of the stable transcripts afforded by transcription from the RNA polymerase III (pol III)-based adenoviral VA1 gene. Importantly, the VA1-chimeric ribozyme is stably expressed with a half-life of almost 6 hours. Using this expression system, we show up to 70% downregulation of the elevated levels of CCR5 receptor in the HOS-CD4.CCR5 cell line. The monocytic cell line PM1 was stably transduced with the chimeric VA1 ribozyme constructs. In these cells, substantial resistance to challenge with an M-tropic but not a T-tropic HIV viral strain was observed, demonstrating specificity in downregulating the CCR5 coreceptor. The VA1-CCR5 ribozyme chimeras described in this study should prove useful in both studies of CCR5 receptor function and therapeutic intervention of monocytotropic HIV-1 infection. The VA1 vector described in this study is well suited for the stable cytoplasmic expression of other ribozyme constructs as well.
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PMID:Downregulation of the CCR5 beta-chemokine receptor and inhibition of HIV-1 infection by stable VA1-ribozyme chimeric transcripts. 1098 19

This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression-HIV-1 RNA level, CD4 cell count, and CD4 percentage-for weight growth failure, cognitive decline, and survival in HIV-infected children. Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment, with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors, higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival, whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation of treatment effects in children.
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PMID:Treatment-mediated changes in human immunodeficiency virus (HIV) type 1 RNA and CD4 cell counts as predictors of weight growth failure, cognitive decline, and survival in HIV-infected children. 1101 Aug 39

This study examined the rate of decline in plasma human immunodeficiency virus type 1 (HIV-1) RNA levels to <400 and <50 copies/mL in children receiving highly active antiretroviral therapy (HAART) consisting of efavirenz, nelfinavir, and 1 or 2 nucleoside reverse-transcriptase inhibitors. Children receiving HAART achieved a plasma HIV-1 RNA level <400 copies/mL by a median of 4 weeks after initiation of therapy and a decline to <50 copies/mL by 20 weeks. Baseline plasma HIV-1 RNA levels affected the likelihood of achieving potent and sustained virus suppression, and children whose CD4 lymphocyte counts increased >70 cells/microL by 20 weeks on therapy were more likely to achieve durable virological and immunological benefit. These data provide time frames for virus suppression after the initiation of HAART that should be useful in evaluating the potential efficacy and durability of response of newly instituted combination antiretroviral therapy in HIV-1-infected children.
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PMID:Patterns of plasma human immunodeficiency virus type 1 RNA response to highly active antiretroviral therapy in infected children. 1106 52

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received </=2 concomitant NRTIs. Eligible patients had CD4 cell counts >50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.
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PMID:Therapy with efavirenz plus indinavir in patients with extensive prior nucleoside reverse-transcriptase inhibitor experience: a randomized, double-blind, placebo-controlled trial. 1113 70

This open-label, multicenter, single-arm clinical trial assessed the 48-week efficacy of a twice-daily triple nucleoside reverse-transcriptase inhibitor regimen containing a lamivudine (150 mg)-zidovudine (300 mg) combination tablet (COM) and abacavir (ABC; 300 mg) in 87 antiretroviral therapy-experienced, protease inhibitor-naive patients infected with human immunodeficiency virus type 1 (HIV-1). At baseline, the median plasma HIV-1 RNA level was 3.10 log(10) copies/mL, and the median CD4 cell count was 506 cells/mm(3). An intent-to-treat&rcolon;observed analysis showed that, at weeks 24 and 48 of treatment, HIV-1 RNA level was <400 copies/mL in 48 (76%) of 63 and 45 (82%) of 55 patients, respectively, and <50 copies/mL in 37 (59%) of 63 and 31 (56%) of 55 patients, respectively. Previous zidovudine or lamivudine use and presence at baseline of the M184V reverse-transcriptase mutation did not impact virologic response. Median CD4 cell counts were maintained above baseline throughout the study. COM plus ABC was generally well tolerated.
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PMID:Twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the TARGET Study. 1117 Sep 82


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