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)

Interleukin 18 (IL-18) is a recently identified cytokine, originally called interferon gamma inducing factor, due to its capacity to induce interferon gamma production in Th1 type cells. IL-18 is expressed by a wide variety of cell types including mononuclear phagocytes, osteoblasts, keratinocytes and adrenal cortex cells. To quantify human IL-18 mRNA expression in small-scale cell samples the authors developed a competitive reverse transcriptase polymerase chain reaction using a competitive template as an internal standard. This assay was demonstrated as a valid, sensitive and precise tool to quantify human IL-18 mRNA expression. IL-18 mRNA expression of primary peripheral blood monocytes, CD4(+)T cells, CD8(+)T cells, B cells and NK cells was assessed by competitive RT-PCR. Basal IL-18 expression could be detected in all types of peripheral blood mononuclear cells (PBMC). The kinetics of IL-18 mRNA expression in PBMC from healthy donors was defined in vitro after monocyte-specific (lipopolysaccharide LPS), T-cell-specific (anti-CD3) and polyclonal-unspecific stimulation (phytohaemagglutinin PHA). Only LPS led to a strong increase of IL-18 mRNA expression peaking after 2 h. These results indicate that IL-18 is expressed constitutionally by all major PBMC subtypes. However, only monocyte specific stimulation resulted in a significant induction of IL-18 mRNA expression suggesting activated monocytes e.g. in inflammation as the main source of IL-18 expression.
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PMID:Quantification of human interleukin 18 mRNA expression by competitive reverse transcriptase polymerase chain reaction. 1034 85

The effect of a male steroid hormone, 5DHT, on the expression of TNF-alpha was examined using a human leukemia T cell line, Jurkat. Cells were treated with 5DHT in the presence or absence of PHA, and RNA was isolated followed by a reverse transcriptase - mediated PCR (RT-PCR) to measure the steady state levels of TNF-alpha mRNA. The treatment of cells with 5DHT resulted in a 50% of decrease in the level of TNF-alpha mRNA compared to that in untreated conditions (basal level). A similar level of reduction of the message by 5DHT was also observed in PHA-stimulated cells. The reduction of the steady state levels of TNF-alpha mRNA in Jurkat cells was a result of destabilization of the gene as demonstrated by actinomycin D treatment; a half-life of TNF-alpha message in 5DHT treated cells and non-treated cells was 1 hr and 2.5 hr, respectively, whereas that in 5DHT/PHA and PHA-treated cells was 3hr and 6hr, respectively.
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PMID:Destabilization of tumor necrosis factor-alpha mRNA by 5-alpha dihydrotestosterone in Jurkat cells. 1082 Nov 25

Ideal treatment of HIV-1 infections should include an agent that can reverse the capacity of the virus to evade destruction by hiding in sanctuaries and by frequently mutating the epitopes it displays. The rapid proliferation of virions during the years of symptomatic quiescence obligates rapid replacement of CD4+ lymphocytes that leads to a gradual attrition of the T lymphocytes needed to control infections. In vitro evidences suggest that, given systematically, certain mitogenic lectins would interfere with HIV-1 invasion of CD4+ cells by blocking gp120 molecules on the viral membrane before activating T lymphocytes subsequent to binding with their Ti/CD3 molecules. The nonspecific nature of antiviral effector cells generated by this activation should circumvent HIV-1 mutations at the same time it reconstitutes depleted T lymphocytes, stimulates myelopoiesis, and reinforces resistance to malignancies and infections prevalent with the immunodeficiency state. Properly coordinating these effects with appropriate combinations of reverse transcriptase and protease inhibitors could theoretically expedite complete elimination of HIV in a timely fashion that shorten the required treatment duration and excludes the detrimental effects of virus mutations. The proper sequence of this treatment should be maximum reduction of the HIV-1 load with drug combinations, control of complicating infection by other means to reduce mitogen-induced tissue necrosis, and addition of systemic PHA-L4 administration regulated to maintain a 5-10 micrograms/mL serum concentration. The antiviral regimen should be continued an undetermined time beyond when HIV-1 is no longer detectable, and systemic L4 administration until satisfactory immunologic and hematologic competences are re-established. Partially-matched mitogen-activated adoptive leukocyte therapy might be additionally helpful.
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PMID:Theoretical benefits of mitogen applications for HIV-1 infections. 1085 67

During highly active antiretroviral therapy (HAART), HIV-1 can still persist in circulating, resting CD4+ T lymphocytes, lymph node mononuclear cells, and seminal cells of patients despite sustained suppression of plasma viremia to undetectable levels. Sanctuary sites where antiretroviral drug penetration is not optimal may allow local HIV-1 infection of cells within and passing through these tissues. Factors such as imperfect drug adherence due to complicated drug regimens may also result in tissue compartments with suboptimal drug concentrations allowing viral replication. We have examined blood monocytes from HIV-1-infected subjects being effectively treated with HAART to determine virus carriage in these cells. Monocytes were purified from peripheral blood of patients with plasma HIV-1 RNA below 50 copies/mL and who had maintained levels of plasma RNA below detection for 3 months or more. Replication-competent virus could be recovered from the majority of monocyte populations by co-culture with CD8-depleted, PHA-activated, peripheral blood mononuclear cells. Sequencing of the reverse transcriptase and protease genes of the recovered viruses did not reveal resistance to both reverse transcriptase and protease inhibitors. Continued new infection of this transitory, circulating population of cells even during prolonged, effective HAART most likely reflects ongoing, low-level HIV-1 replication within cellular reservoirs and sanctuary sites in the body.
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PMID:HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. 1098 50

RANTES and MCP-1 represent a link between the activation of monocytes, lymphocytes, basophils, mast cells and eosinophils in inflammatory disorders, such as the late phase allergic reaction. These C-C chemokines also play a role in regulating Th cell cytokine production and leukocyte trafficking. In this study, we determined the expression and secretion of RANTES and MCP-1 from PHA-activated PBMC of healthy and atopic subjects with no symptoms. Levels of RANTES from PHA-activated PBMC of atopic patients were higher, at 18 and 24 h incubations (42+/-5.5 and 48+/-4), compared to controls (20+/-4 and 35+/-4), respectively; while MCP-1 was not (12+/-3 and 17+/-3) compared to controls (10.5+/-3 and 15+/-2), respectively. This effect was also revealed on RANTES mRNA expression, as determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, PHA-activated PBMC of atopic subjects produce more IL-4 (five times more) than healthy subjects, while IFN-gamma did not vary. RANTES, compared to MCP-1, may have more influence on signal transduction pathways, either in physiologic or inflammatory states and may induce profound effects on the regulation of cell activity. The differential production of RANTES and MCP-1 may lead to diverse regulation of the function and development of cells involved in the allergic response. These studies emphasize the importance of chemokine selectivity during inflammation.
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PMID:Differential expression and secretion of RANTES and MCP-1 in activated peripheral blood mononuclear cell cultures of atopic subjects. 1122 7

The objective of this work was to test the antiviral activity of a potent nucleoside reverse transcriptase inhibitor, 3'-fluoro-3'-deoxythymidine (FLT), on both a wild-type human immunodeficiency virus (HIV-1) isolate and multidrug-resistant HIV-1 patient isolates. Drug-resistant viral isolates were selected on the basis of four different categories of well-characterized and representative multidrug-resistant mutants. The isolates included three variants containing 151M alone or in combination; three variants containing 215Y and 41L, 67N, 184V, 210W, and 219N in combination; two insertion mutant viruses (69 + EA and 69 + SA); and two deletion mutant viruses (del67NG and del67GS), the latter two groups both also containing other significant mutations. The activity of FLT and AZT against these isolates was determined by drug susceptibility assays and by measuring viral antigen p24 by ELISA. The cytotoxicity of FLT and AZT was assessed in PHA-stimulated PBMCs. Development of resistant mutants under FLT pressure was attempted by passaging HIV-1 isolates in SupT1 cells and stepwise increasing the concentration of FLT. The multidrug-resistant mutant HIV-1 isolates exhibited 7-fold to >100-fold increased resistance to AZT, but showed IC(50) values for FLT of 0.0014-0.0168 microM, which were lower than or similar to that of wild type (0.0075 microM). The cellular cytotoxicities of FLT and AZT fell into a similar range in PBMCs. The development of HIV mutants resistant to FLT appeared to be slower than for other RT inhibitors. HIV isolates with mutations resulting in multidrug resistance had no evidence of resistance to FLT. FLT may be useful in salvage therapies for patients harboring resistant strains and a reassessment of its therapeutic potential seems required.
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PMID:Anti-HIV type 1 activity of 3'-fluoro-3'-deoxythymidine for several different multidrug-resistant mutants. 1128 8

We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.
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PMID:Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma. 1128 17

In the present study, for the first time, PDE4 subtypes were identified and semi-quantified in both CD4 and CD8 lymphocytes from healthy and asthmatic individuals. CD4 and CD8 lymphocytes from healthy and mild asymptomatic asthmatic subjects (receiving beta-agonist therapy only) were isolated from peripheral venous blood using appropriate antibody coated paramagnetic beads. PDE4 subtypes and beta-actin were identified by digoxigenin (DIG)-labelling reverse transcriptase-polymerase chain reaction and semi-quantified by DIG-detection enzyme-linked immunosorbance assay. In CD4 and CD8 lymphocytes PDE4A, PDE4B and PDE4D were detected, with no significant differences observed between healthy and asthmatic groups. In CD8 lymphocytes, enzyme subtype expression was lower and showed more intersubject variability. In functional studies investigating the effects of various PDE inhibitors on PHA-induced proliferation of mononuclear cells from healthy and asthmatic subjects, CDP840 (0.03 - 10 microM), rolipram (0.1 - 10 microM) and theophylline (10 microM - 1 mM) inhibited PHA-induced proliferation of mononuclear cells from healthy and asthmatic subjects in a concentration-dependent manner, although no significant difference was observed between the groups investigated. In additional studies, total monocyte cyclic AMP PDE activity was investigated in cells isolated from asthmatic subjects both prior to and 24 h after allergen challenge. Total monocyte cyclic AMP PDE activity remained unaffected following challenge of asthmatic subjects with either house dust mite or cat dander and was inhibited in a concentration-dependent manner by rolipram (0.01 - 100 microM) both before and after allergen challenge.
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PMID:Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects. 1142 97

Because prevention of heterosexual HIV transmission is not always possible, it is important to develop effective strategies of postexposure prophylaxis (PEP). Since in vivo comparison of drug potency is difficult, we developed an in vitro model with cells resembling primary targets during sexual transmission: monocyte-derived dendritic cells (MO-DCs), Langerhans cells (MO-LCs), and resting autologous CD4(+) T cells. Nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively) were evaluated for their antiviral activity, when added immediately after infection or at a later time point. In parallel, their immune-suppressive effect was examined by measuring inhibition of mixed MO-DC/allogeneic CD4(+) T cell cultures. Most RTIs potently inhibited HIV replication, even if added 24 hr after infection (representing PEP). The sensitivity to antiretroviral drugs was similar in HIV-infected MO-DCs and MO-LCs, but decreased in cocultures with resting autologous CD4(+) T cells. The NNRTIs efavirenz and UC-781 as well as the NRTIs AZT, 3TC, and d4T showed a similar high potency in MO-DC plus autologous CD4(+) T cell cocultures as compared with CEM T cells, whereas their activity in phytohemagglutinin/interleukin 2 (PHA/IL-2)-activated CD4(+) T cells was lower. The dideoxynucleoside RTI abacavir as well as the phosphonates (R)-PMPA and PMEA were more active in infected MO-DCs as compared with either CEM T cells or PHA/IL-2 activated CD4(+) T cells. Infection in cocultures of MO-DCs and autologous CD4(+) T cells could be aborted in a proportion of the cultures, with high concentrations of PMEA and/or efavirenz, but not with AZT. Suppressive activity in mixed leukocyte cultures was observed only at very high concentrations of RTI. Our data suggest that cocultures of MO-DCs and autologous CD4(+) T cells can be used as a possible in vitro model to explore protocols for PEP after sexual HIV transmission.
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PMID:Activity of reverse transcriptase inhibitors in monocyte-derived dendritic cells: a possible in vitro model for postexposure prophylaxis of sexual HIV transmission. 1239 48

Recent development of tuberculosis in Japan tends to converge on a specific high risk group. The proportion of tuberculosis developing particularly from the compromised hosts in the high risk group is especially high. At this symposium, therefore, we took up diabetes mellitus, gastrectomy, dialysis, AIDS and the elderly for discussion. Many new findings and useful reports for practical medical treatment are submitted; why these compromised hosts are predisposed to tuberculosis, tuberculosis diagnostic and remedial notes of those compromised hosts etc. It is an important question for the future to study how to prevent tuberculosis from these compromised hosts. 1. Tuberculosis in diabetes mellitus: aggravation and its immunological mechanism: Kazuyoshi KAWAKAMI (Department of Internal Medicine, Division of Infectious Diseases, Graduate School and Faculty of Medicine, University of the Ryukyus). It has been well documented that diabetes mellitus (DM) is a major aggravating factor in tuberculosis. The onset of this disease is more frequent in DM patients than in individuals with any underlying diseases. However, the precise mechanism of this finding remains to be fully understood. Earlier studies reported that the migration, phagocytosis and bactericidal activity of neutrophils are all impaired in DM patients, which is related to their reduced host defense to infection with extracellular bacteria, such as S. aureus and E. colli. Host defense to mycobacterial infection is largely mediated by cellular immunity, and Th1-related cytokines, such as IFN-gamma and IL-12, play a central role in this response. It is reported that serum level of these cytokines and their production by peripheral blood mononuclear cells (PBMC) are reduced in tuberculosis patients with DM, and this is supposed to be involved in the high incidence of tuberculosis in DM. Our study observed similar findings and furthermore indicated that IFN-gamma and IL-12 production by BCG-stimulated PBMC was lower in poorly-controlled DM patients than that in well-controlled DM patients and healthy subjects. Thus, these clinical data suggest that the high incidence of tuberculosis in DM patients is due to the impaired production of Th1-related cytokines. However, direct evidences to prove this possibility remain to be obtained. In 1980, Saiki and co-workers reported that host defense and delayed-type hypersensitivity response to M. tuberculosis was hampered in a mouse DM model established by injecting streptozotocin (Infect Immun. 1980; 28: 127-131). We followed their investigation with the similar observations. Interestingly, levels of IFN-gamma and IL-12 in serum, lung, liver and spleen after infection were significantly reduced in DM mice when compared with those in control mice. Considered collectively, these results strongly suggest that the reduced production of Th1-related cytokines leads to the susceptibility of DM to mycobacterial infection. However, it remains to be understood how DM hampers the synthesis of Th1-related cytokines. In our preliminary study, the production of these cytokines by PBMC from DM patients and healthy subjects was not affected under a high glucose condition. Thus, it is not likely that the increased level of glucose directly suppresses the cell-mediated immune responses. Further investigations are needed to make these points clear. 2. A study of gastrectomy cases in pulmonary tuberculosis patients: Takenori YAGI (Division of Thoracic Disease, National Chiba-Higashi Hospital). Patients who have undergone gastric resection are considered at increased risk of developing pulmonary tuberculosis. I have investigated the role played by gastrectomy in giving rise to pulmonary tuberculosis. Of 654 pulmonary tuberculosis patients admitted to National Chiba-Higashi Hospital from January 1999 to December 2001, 55 patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The incidence of gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of gastric resection was 50.2 +/- 16.6 years, and the mean interval from gastrectomy to pulmonary tuberculosis was 13.6 +/- 11.0 years. On admission to our hospital, 34 out of 55 cases were smear positive by sputum examination for acid-fast bacilli and 39 cases had cavitary lesions on chest X-ray. Gastrectomy was done due to carcinoma of the stomach in 31 cases, gastric and/or duodenal ulcer in 21 cases, adenomatous polyp in two cases, and accidental injury in one case. 52 patients improved, but three cases died due to pulmonary tuberculosis. No one had recurrence of carcinoma of the stomach. Body weight, Body Mass Index, Prognostic Nutritional Index (PNI; 10x serum albumin concentration +0.005 x peripheral lymphocyte count) which was proposed by Onodera, serum albumin level and serum total cholesterol level were lower in the gastrectomy group than in the non-gastrectomy group. I calculated the odds of tuberculosis among gastrectomy patients to be 3.8 times that of appropriate controls. This study confirms that gastrectomy is one of the risk factor(s) of tuberculosis. However, whether gastrectomy in itself is a risk factor or whether it is secondarily associated with another risk factor such as underweight status and/or inadequate nutrition following surgery remains unclear. 3. Immunodefficiency and tuberculosis in dialysis patients: Hajime INAMOTO (Division of Dialysis, Keio University School of Medicine). The patients who have renal insufficiency is fatal, but they can live much longer by dialysis. The number of lymphocytes of the patients whose serum creatinine was 10 mg/dl or more has decreased to about 50% of the people who have normal kidney. When the lymphocyte was cultured after it was stimulated with PHA, the DNA synthesis of the patients' lymphocyte was much lower than that of the modest people's. In the dialysis food, the nutrient such as vitamins, minerals, etc. were lacked. The density of the serum albumin of the dialysis patient has decreased. Many of them were thin when their BMI was examined. The size of the patients' erythema by the tuberculin test has become small. There were many patients receiving dialysis with erythema but no induration. It means that the delayed skin reaction specific to Mycobacterium tuberculosis has decreased among the dialysis patients. The morbidity rate, the mortality rate and the prevalence of tuberculosis was much higher than the general population. The anamnesis of tuberculosis was also high. Most of those tuberculosis patients appear the disease from the period immediately before the beginning of dialysis to one year after that. That is also the period that patients' number of peripheral blood lymphocyte decreased and the tuberculin reaction positivity rate fell sharply. During the dialysis patients, pulmonary tuberculosis with cavities was minority and extrapulmonary tuberculosis and miliary tuberculosis were remarkably many. People with large reaction against the tuberculin test were better prognosis than those with smaller reaction. It was thought that anorexia, weakening, and a weight decrease were seen when the immunity decreased. At the end stage of renal failure, kidney shrink, vitamin D activation becomes difficult, and the low calcium blood syndrome appears. The calcification of tuberculoma is absorbed, soft tuberculoma becomes baring, the caseation abscess melts, and the endogenous infection occurs. The cell immunity has decreased, and tuberculosis attacks. It might be such circumstances that tuberculosis happen frequently at the dialysis introduction period. There are a lot of cases that the caseation necrosis is a little, and the formation of tuberculoma is bad in the pathology opinion. Due to the decrease in the cell immunity, cavities are not formed easily. It is easy to stay in the leaching lesion so that anti-tuberculosis drugs are much effective, and the patients recover easily. However, if the treatment is delayed, it is fatally because hematogenous metastasis are easy to occur and become miliary tuberculosis. 4. AIDS and tuberculosis: Hideaki NAGAI (Department of Respiratory Diseases, National Tokyo Hospital). With AIDS patients with tuberculosis, there are the following problems on the treatment. (1) The adverse reactions by antituberculosis drugs tend to occur in AIDS patients. Eleven of 33 AIDS patients with tuberculosis had the adverse reactions (skin rash, fever, liver dysfunction) considered to be due to antituberculosis drugs. It is a very large burden for the HIV infected persons to take simultaneously antituberculosis drugs, medicines for opportunistic infections, and anti-HIV medicines. Since many medicines are taken, it is difficult to determine which drug is the cause once an adverse reaction occurs and all medicines should be often stopped. (2) The combined use with rifampicin (RFP) is difficult for the protease inhibitors and nonnuclear acid reverse transcriptase inhibitors. RFP induces cytochrome P-450 in liver, accelerates the metabolism of some concomitant drug agents, and reduces blood concentration them remarkably. When starting the two above-mentioned medicines during tuberculosis treatment, RFP should be changed to rifabutin (RFB) which has less induction of P-450 than RFP. However, some procedures are required for acquisition of RFB and it is a little complicated in Japan. CDC mentioned the combined use with RFP and efavirenz (EFV) is possible. So, the treatment with EFV and RFP is recently chosen. However, the monitor of the blood concentration of EFV is required, and the dose of EFV should be increased if it is a low value. (3) When a highly active antiretroviral therapy (HAART) is given to AIDS patients with tuberculosis, transient worsening of tuberculosis may develop after about two weeks. (ABSTRACT TRUNCATED)
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PMID:[Tuberculosis in compromised hosts]. 1467 50


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