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)

An impediment to the development of efficacious vaccines for bovine tuberculosis has been the failure to demonstrate strong associations between immune function and protective immunity. Cytokine gene expression in response to Mycobacterium bovis (M. bovis) infection was evaluated to identify correlates of immunity. Ten Holstein calves were infected with M. bovis by intratonsillar inoculation. Five uninfected animals served as controls. At 15, 30, 60 and 85 days post-infection (dpi) peripheral blood mononuclear cells (PBMC) were isolated and stimulated with either purified protein derivative of M. bovis (PPD), a recombinant fusion protein comprised of 6 kDa early secretory antigenic target and 10 kDa culture filtrate antigen (rESAT6:CFP10), or PBS. After a 16 h incubation period, total leukocyte RNA was isolated and gene expression evaluated using reverse transcriptase real-time PCR. In addition, gene expression adjacent to gross lesion in the retropharyngeal lymph node (LN) was analyzed. Pathology was evaluated at necropsy. Expression of IFN-gamma, TNF-alpha, iNOS and IL-4 by PBMC increased in response to infection, whereas, IL-10 expression decreased. Differences in gene expression between PBMC from infected and uninfected animals was greatest at 30 dpi. Infected animals were divided into two groups based on pathology. Animals in the low pathology group had lesions primarily in LN of the head; whereas, animals in the high pathology group also had lesions in the lungs and lung associated LN. Gene expression in PBMC and LN was compared between animals in the high and low pathology groups. Cells from animals in the high pathology group expressed more IFN-gamma, TNF-alpha, iNOS and IL-4 than did animals in the low pathology group at early time points. IL-10 gene expression decreased with time in PBMC from animals in the high pathology group. At 85 dpi, animals in the high pathology group expressed twofold less IL-10 mRNA than did animals in the low pathology group and the uninfected controls. IFN-gamma and iNOS gene expression were significantly greater in tissues from infected animals compared to tissues from uninfected animals. The pathological outcome of M. bovis infection of cattle may be established early after infection since expression of both the TH1 and TH2 cytokines were differentially expressed by animals in the high and low pathology groups at early time points. In addition, more robust immunological responses were associated with increased pathology. These results suggest that early immune responses play a critical role in establishing the pathological outcome.
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PMID:Associations between cytokine gene expression and pathology in Mycobacterium bovis infected cattle. 1762 95

The goals of tuberculosis control are to cure active disease, prevent relapse, reduce transmission and avert the emergence of drug resistance. However, since the 1960s, there have been few developments in available therapies. Currently available agents are complicated by numerous side-effects, drug interactions and the need for a long duration of therapy. Rifampicin-containing regimes lead to hepatic enzyme induction which can complicate or preclude the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors in patients infected with the human immunodeficiency virus. Furthermore, emerging drug resistance has complicated management for many patients and clinicians. Therefore, new chemotherapeutic agents are urgently needed. Existing antimicrobials are emerging as potent antituberculous agents. Recent studies have demonstrated the antituberculous activity of newer fluoroquinolones including levofloxacin, moxifloxacin, and gatifloxacin. Their use as first line antituberculous agents is currently under investigation. Furthermore, the oxazolidinones linezolid and PNU-100480 have been shown to have antituberculous activity in addition to their antibacterial effects. Several other agents are currently being developed for the treatment of tuberculosis. These agents include diarylquinolones (R207910), nitroimidazopyrans (PA-824, OPC-67683), ethambutol analogues (SQ109), cerulenin, trans-cinnamic acid, macrolides, pyrroles (LL3858), long-acting rifamycins and inhaled interferon-gamma. Furthermore, vaccines are being explored for pre-exposure and post-exposure use. This review will describe therapeutic developments in the management of tuberculosis, highlighting mechanisms of action of new pharmacological agents and their potential for clinical use.
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PMID:Novel agents in the management of Mycobacterium tuberculosis disease. 1769 42

Triple nucleoside reverse transcriptase inhibitors are recommended as an alternative regimen for HIV-infected patients undergoing tuberculosis treatment in resource-limited settings. Few data exist on the efficacy of such regimens in tuberculosis patients. In 34 tuberculosis/HIV-co-infected patients treated with zidovudine/lamivudine/abacavir, 76% achieved HIV RNA less than 50 copies/ml at 24 weeks. No cases of hypersensitivity or immune reconstitution syndrome were observed. These data support the continuing evaluation of nucleoside-based antiretroviral regimens as an alternative treatment for this population.
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PMID:Early virological response of zidovudine/lamivudine/abacavir for patients co-infected with HIV and tuberculosis in Uganda. 1772 Nov 7

PPE44 is a member of the Mycobacterium tuberculosis PPE proteins, a polymorphic family of 69 glycine-rich proteins that predictively represent a source of antigenic variation. The genetic diversity of gene ppe44 among clinical isolates has been studied. No genomic polymorphism of ppe44 was found by a PCR-restriction fragment length polymorphism assay using three restriction enzymes. Nucleotide sequencing of gene ppe44 of a number of isolates, selected to represent the major phylogenetic lineages of M. tuberculosis, showed no nucleotide substitution, with the exception of isolates of the Beijing genotype. These findings indicate that gene ppe44 is basically conserved among M. tuberculosis strains. The expression of gene ppe44 was then determined at the transcriptional level by a real-time reverse transcriptase PCR assay. Extremely high quantitative variations in ppe44 expression were found among the isolates; ppe44 expression of the Beijing strains was significantly higher than the non-Beijing strains. To test whether differential expression of gene ppe44 has the potential to provide a dynamic antigen display, antibodies to PPE44 were titered in the sera of M. tuberculosis-infected subjects. Variation of antibody response to PPE44 was found with regard to both antibody titers and the proportion of responding subjects. These results indicate that the differential expression of genes ppe could influence the host's immune responsiveness, thus having implications in the immunopathogenesis of tuberculosis.
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PMID:Variation of the expression of Mycobacterium tuberculosis ppe44 gene among clinical isolates. 1772 53

Access to antiretroviral therapy has expanded in many developing countries, including India. The standard first-line regimens consist of a combination of two nucleoside reverse transcriptase inhibitors and a nonnucleoside reverse transcriptase inhibitor, in a fixed drug combination. Data regarding resistance to these drugs are scarce, especially in children. We evaluated the pattern of polymorphism and potential drug resistance mutations (DRMs) in HIV-1 isolates from 48 children naive to antiretroviral therapy attending the outpatient clinics of the Tuberculosis Research Center in Chennai. The samples were subjected to genotyping of reverse transcriptase (RT) and protease genes. All the samples showed significant polymorphisms in both RT and protease genes, but none had major DRMs. The currently recommended generic first-line antiretroviral drug combination is an appropriate treatment strategy for HIV-1-infected children in India.
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PMID:Characterization of HIV-1 isolates from antiretroviral drug-naive children in southern India. 1791 7

In the early stage of Mycobacterium tuberculosis infection, macrophages, in cooperation with interferon-gamma, a Th1 effector, are the first line of defense. Interleukin (IL)-4, a Th2 effector, is known to downregulate interferon-gamma. It is believed that the expression levels of IL-4 and its splicing variant-IL-4delta2 might be associated with Mycobacterium tuberculosis infection and chest radiographic patterns. The IL-4 and IL-4delta2 expressions in stimulated peripheral blood mononuclear cells of 76 tuberculosis patients, 48 pneumonic patients. and 36 healthy control subjects were evaluated by nested reverse transcriptase-polymerase chain reaction, and the expression of glyceraldehydes-3-phosphate dehydrogenase was used as an internal reference. The results showed that IL-4 mRNA expression was significantly decreased in patients with tuberculosis and nontubercular pneumonia compared with that in controls. The IL-4delta2 mRNA expression was positively correlated with IL-4 mRNA expression in all cases. The ratio of IL-4delta2 to IL-4 mRNA expression in tubercular patients with a cavity on chest radiography was significantly lower than that in patients without a chest cavity. In conclusion, the ratio of IL-4delta2 to IL-4 mRNA expression may play a key role in disease severity for patients with pulmonary tuberculosis. From our observations, the IL-4 mRNA expression efficiency was attenuated in patients with pulmonary infection, either tuberculosis or pneumonia.
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PMID:Efficiency of interleukin-4 expression in patients with tuberculosis and nontubercular pneumonia. 1796 71

The introduction of highly active antiretroviral therapy (HAART) in 1996 dramatically changed the course of HIV infection. This therapy involves the use of at least three agents from two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Nine drugs containing PIs are clinically available: the first generation ones, saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir, and the second generation ones, fosamprenavir (the amprenavir prodrug), lopinavir, atazanavir, and tipranavir. Many other compounds are in advanced clinical evaluation, such as among others TMC-114, whereas a lot of different other effective HIV protease inhibitors were reported, mainly by using amprenavir and TMC-114 as lead molecules. The main goals of research in this field are: (i) the design of better pharmacological agents, devoid of severe side effects, resistance problems and with simple administration schedules (preferably once daily), and (ii) achieving eradication of the virus, and possibly, a definitive cure of the disease. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to PI drugs may be managed better by taking them into account (such as for example ritonavir boosting of other PIs which reduces dosages and administration schedules of these drugs). Except for being highly effective in the treatment of HIV infection, recent reports showed this class of drugs to be effective as antitumor agents, as antibacterials (for example against Mycobacterium tuberculosis infection), antifungals (against Candida albicans), antimalarials, antiSARS and anti-influenza agents.
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PMID:Inhibitors of HIV-1 protease: current state of the art 10 years after their introduction. From antiretroviral drugs to antifungal, antibacterial and antitumor agents based on aspartic protease inhibitors. 1804 20

In sub-Saharan Africa, human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. Sub-Saharan Africa has seen the woeful failure of World Health Organization (WHO) targets of detecting 70% of the infectious cases of tuberculosis and curing > or =85%. Current treatment of Mycobacterium tuberculosis in most resource limited settings is comprised of a four-drug initial antituberculosis regimen for two months, followed by either a two-drug continuation phase of antituberculosis regimen for four months or six months depending on the medications. Many countries in sub-Saharan Africa are scaling up with highly active antiretroviral therapy (HAART), using one of the first-line regimens that consist of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our current HAART regimen and antituberculosis drugs continue to give us a therapeutic challenge in terms of adverse effects, drug-drug interactions and immune reconstitution inflammatory syndromes. Scientific research is needed in the areas of diagnosis, treatment and prevention of tuberculosis in sub-Saharan Africa. Such research could be facilitated due to greater availability of funding than a decade ago.
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PMID:HIV and tuberculosis coinfection: inextricably linked liaison. 1822 80

The heterodimeric cytokine IL-12 (composed of a p35 and a p40 subunit) is produced primarily by monocytes, macrophages and B cells. In vitro and in vivo experiments have demonstrated the crucial role of IL-12 in initiating and establishing both innate immunity and T cell-mediated resistance to intracellular pathogens, including Leishmania donovani, Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. Assessment of cytokine expression has thus become crucial to understand host responses to infections. In this study, by using the reverse transcriptase-real time PCR we developed a highly specific and sensitive assay to quantitatively evaluate IL-12p40 mRNA transcription levels in peripheral blood mononuclear cells (PBMCs) stimulated with PHA vs. unstimulated cells. We also used the ELISA to evaluate bioactive IL-12 release in culture supernatants. We provide evidence that IL-12 p40 mRNA levels were significantly up-regulated in PHA-activated PBMCs. These results were correlated with data of IL-12 levels obtained by ELISA.
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PMID:Quantitative evaluation of interleukin-12 p40 gene expression in peripheral blood mononuclear cells. 1830 39

Cytokine mRNA expression of pro-inflammatory cytokines, i.e., interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and anti-inflammatory cytokines, i.e., interleukin-4 (IL-4), interleukin-10 (IL-10) was quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in cattle infected with different doses (1-1000 colony-forming units (cfu)) of Mycobacterium bovis. RNA was extracted from the Hepes glutamic acid buffer mediated organic solvent protection effect (HOPE) fixed lymph node tissues using Trizol method. The expression levels of all the four cytokines gradually increased in cattle infected with 1 cfu-1000 cfu. Statistical significance (P<0.05) was observed for the cytokines IFN-gamma, IL-4 and IL-10 between the cattle infected with 1 cfu and 1000 cfu. Though there was an increase in the expression levels of TNF-alpha from cattle infected with 1 cfu-1000 cfu, this difference in expression was not statistically significant (P>0.05). The increase in the levels of IFN-gamma indicates that the host may be responding to control the infection and the increased level of IL-4 and IL-10 which are anti-inflammatory cytokines, suggests that these cytokines are trying to protect the host by reducing the inflammation and also by controlling the levels of TNF-alpha (the cytokine that may cause tissue damage).
Tuberculosis (Edinb) 2008 Nov
PMID:Cytokine mRNA expression in cattle infected with different dosages of Mycobacterium bovis. 1867 70


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