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)

Chronic use of antiretrovirals (ARVs) to treat HIV infection, along with more prolonged patient survival, has been associated with an increase in adverse drug effects in HIV-infected patients on treatment. It has been proposed that some of these adverse effects (including myopathy, cardiomyopathy, anaemia, hyperlactataemia/ lactic acidosis, pancreatitis, polyneuritis and lipodystrophy) could be mediated by mitochondrial (mt) toxicity. From the experimental data, it has been proposed that nucleoside analogue reverse transcriptase inhibitors (NRTIs) also inhibit gamma-polymerase, the enzyme devoted to replicate (and, to a lesser extent, repair) mtDNA. It is now widely accepted that the use of most NRTIs in HIV-infected patients is associated with mtDNA depletion. Although cross-sectional studies suggest that certain ARVs, especially stavudine, are more toxic to mitochondria, the differences among different highly active ARV therapy (HAART) schedules detected in the analysis of longitudinal studies are not so clear. These types of study in previously untreated individuals suggest that the greatest mtDNA loss appears at the beginning of the treatment. Conversely, in ARV-experienced patients, the potential beneficial effects of HAART changes in terms of mtDNA content remain controversial and must be further investigated. Functional studies accompanying genetic investigations are needed for the correct pathogenic interpretation of the mtDNA abnormalities.
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PMID:Mitochondrial studies in HAART-related lipodystrophy: from experimental hypothesis to clinical findings. 1615 8

Lentiviral vectors are being developed to satisfy a wide range of currently unmet medical needs. Vectors destined for clinical evaluation have been rendered multiply defective by deletion of all viral coding sequences and nonessential cis-acting sequences from the transfer genome. The viral envelope and accessory proteins are excluded from the production system. The vectors are produced from separate expression plasmids that are designed to minimize the potential for homologous recombination. These features ensure that the regeneration of the starting virus is impossible. It is a regulatory requirement to confirm the absence of any replication competent virus, so we describe here the development and validation of a replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based vectors. The assay is based on the guidelines developed for testing retroviral vectors, and uses the F-PERT (fluorescent-product enhanced reverse transcriptase) assay to test for the presence of a transmissible reverse transcriptase. We have empirically modelled the replication kinetics of an EIAV-like entity in human cells and devised an amplification protocol by comparison with a replication competent MLV. The RCL assay has been validated at the 20 litre manufacturing scale, during which no RCL was detected. The assay is theoretically applicable to any lentiviral vector and pseudotype combination.
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PMID:A replication competent lentivirus (RCL) assay for equine infectious anaemia virus (EIAV)-based lentiviral vectors. 1620 18

According to the World Health Organization guidelines, a non-nucleoside reverse transcriptase inhibitor (NNRTI) along with two nucleoside reverse transcriptase inhibitors (NRTI) is the treatment of choice as first-line antiretroviral therapy. The results of the 2NN and different cohort studies performed in developed countries do not provide sufficient evidence by which to select between nevirapine and efavirenz as the first-line NNRTI for antiretroviral therapy in Africa. The current first-line NNRTI-containing antiretroviral therapy regimens used in Africa are certainly not ideal. Nevirapine interacts with rifampicin and therefore is not indicated in patients with tuberculosis. On the other hand, efavirenz should not be given to pregnant women. NNRTI-containing regimens may be less effective in women who received nevirapine monotherapy at delivery. Stavudine, used in the nucleoside backbone, may lead to lipoatrophy, lactic acidosis and polyneuritis. Zidovudine may cause serious anemia. Mainly because of cost considerations, the generic fixed-drug combination of nevirapine plus two NRTI seems at the moment to be the best choice. It is clear, however, that antiretroviral programs should not rely only on this combination for initial antiretroviral treatment. Most importantly, more HIV clinical trials need to be conducted in Africa, and African cohorts of patients on antiretroviral therapy need to be established in order to develop recommendations that are evidence based.
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PMID:First-line antiretroviral therapy in Africa--how evidence-base are our recommendations? 1630 62

The Chinese equine infectious anemia virus (EIAV) donkey-leukocyte attenuated vaccine (DLV) provides a unique natural model system to study the attenuation mechanism and immunological control of lentivirus replication. Critical consensus mutations were identified between virulent Chinese EIAV strains and vaccine strains. Based on a full-length infectious clone of EIAV vaccine strain pLGFD3, two molecular clones, mFD5-4-7 and mFD7-2-11, were successfully constructed, in which 4 and 6 critical consensus mutations in the env gene of the vaccine strain were point-mutated to the wild-type sequence, respectively by an overlap PCR mutagenesis strategy. The infectivity, virulence, and pathogenesis of the constructed clones were investigated in vitro using a reverse transcriptase assay, an indirect immunofluorescence assay, observation of cytopathogenic effect, and virion observation as well as in vivo by inoculation of animals with the resulting infectious clones. The pathogenic symptoms in horses inoculated with mFD7-2-11 were more severe than those inoculated with mFD5-4-7, whereas no pathogenic symptoms were detected in animals inoculated with their parental clone pLGFD3 strain. The results indicate that the consensus mutation residues of the env region involved in this study play significant roles in the virulence and pathogenicity of EIAV. This will contribute to the elucidation of the attenuating and protective mechanisms of the Chinese EIAV vaccine.
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PMID:Combined amino acid mutations occurring in the envelope closely correlate with pathogenicity of EIAV. 1650 85

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) have substantially lowered the risk of the mother-to-child transmission of HIV. Evidence of mitochondrial toxicity in vitro, in animal models and in adult HIV-infected patients, has raised concern about the perinatal safety of these antiretrovirals. In zidovudine-exposed, but HIV-uninfected infants, transient anaemia and additional long-term blood abnormalities (neutropenia, thrombopenia and lymphopenia) and hyperlactatemia have been documented. The overall risk of mortality and congenital abnormalities does not appear to be increased, but rare mitochondrial events cannot be excluded for lack of statistical power. French data suggest an above background incidence of mitochondrial symptomatology. Preclinical data demonstrate zidovudine also to be a carcinogen. Long-term systematic follow-up of exposed babies in large cohorts is needed, as are randomised trials with NRTIs carrying a lower risk of mitochondrial toxicity.
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PMID:Mitochondrial disease in the offspring as a result of antiretroviral therapy. 1661 Sep 67

We report the case of a 17-year-old male who was admitted to the emergency department in cardiogenic shock and multiorgan failure due to fulminant myocarditis. The following days the patient developed anemia, thrombocytopenia, and hepatosplenomegaly. Bone marrow examination showed many mature histiocytes with active hemophagocytosis. Nested reverse transcriptase-PCR molecular analysis of blood samples and sequencing of the amplified alleles confirmed enteroviral infection. Our patient was treated with inotropic agents and immunoglobulin, and recovered completely. This is the first report that documents concomitant presentation of fulminant myocarditis and hemophagocytic syndrome due to enteroviral infection.
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PMID:Enterovirus-induced fulminant myocarditis and hemophagocytic syndrome. 1673 67

Sixty-one birds of prey admitted to The Wildlife Center of Virginia (WCV; Waynesboro, Virginia, USA) from June to November 2003 were tested for West Nile virus (WNV) infection. Choanal and/or cloacal swabs were obtained and submitted to Virginia's Division of Consolidated Laboratory Services (Richmond, Virginia, USA) for analysis with real-time reverse transcriptase polymerase chain reaction (RT-PCR). Forty birds of prey were positive for WNV by RT-PCR. Five avian families and nine species of raptors were represented, with great horned owls (Bubo virginianus) and red-tailed hawks (Buteo jamaicensis) most frequently affected. Presenting clinical signs were consistent with previous reports of WNV infection in raptors; however, these differed between species. Of WNV positive birds, nonspecific signs of illness were the most common clinical findings, particularly in red-tailed hawks; signs included dehydration (n = 20), emaciation (n = 18), and depression (n = 15). Neurologic abnormalities were frequently identified, especially in great horned owls, and included head tremors (n = 17), ataxia (n = 13), head incoordination (n = 7), torticollis (n = 3), nystagmus (n = 3), and head tilt (n = 3). Great horned owls exhibited anemia and leukocytosis with heterophilia, eosinophilia, and monocytosis consistent with chronic inflammation. Red-tailed hawks were anemic with a heterophilic leukocytosis and regenerative left shift. The majority of WNV cases occurred during August and September; there was a marked increase in the number of raptors admitted to WCV during these months followed by a marked decrease during October, November, and December. This pattern differed from mean monthly admissions during the previous 10 years and suggests a negative impact on local raptor populations. The effects of WNV on avian populations are largely unknown; however, because of their ecological importance, further investigation of the effects of WNV on raptor populations is warranted.
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PMID:West Nile virus in raptors from Virginia during 2003: clinical, diagnostic, and epidemiologic findings. 1687 Aug 56

Erythropoietin (Epo) and its cognate receptor (EpoR) are required for maintaining adequate levels of circulating erythrocytes during embryogenesis and adulthood. Here, we report the functional characterization of the zebrafish epo and epor genes. The expression of epo and epor was evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and whole-mount in situ hybridization, revealing marked parallels between zebrafish and mammalian gene expression patterns. Examination of the hypochromic mutant, weissherbst, and adult hypoxia-treated hearts indicate that zebrafish epo expression is induced by anemia and hypoxia. Overexpression of epo mRNA resulted in severe polycythemia, characterized by a striking increase in the number of cells expressing scl, c-myb, gata1, ikaros, epor, and betae1-globin, suggesting that both the erythroid progenitor and mature erythrocyte compartments respond to epo. Morpholino-mediated knockdown of the epor caused a slight decrease in primitive and complete block of definitive erythropoiesis. Abrogation of STAT5 blocked the erythropoietic expansion by epo mRNA, consistent with a requirement for STAT5 in epo signaling. Together, the characterization of zebrafish epo and epor demonstrates the conservation of an ancient program that ensures proper red blood cell numbers during normal homeostasis and under hypoxic conditions.
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PMID:Functional conservation of erythropoietin signaling in zebrafish. 1757 87

Although antiretroviral therapy (ART) is critical for preventing mother-to-child transmission of HIV, concern has been raised about the possibility that it may cause mitochondrial dysfunction in infants. There is adequate evidence for a mechanism by which exposure to nucleoside reverse transcriptase inhibitors (NRTIs) could lead to mitochondrial dysfunction; animal studies have shown evidence of mitochondrial dysfunction in the offspring of animals treated with NRTIs and mitochondrial disorders occur in adults treated with NRTIs. This systematic review synthesises the published research on mitochondrial dysfunction and disorders in infants exposed to HIV and antiretrovirals. We found conflicting evidence regarding the possible association of in utero ART exposure with mortality and morbidity due to mitochondrial dysfunction. ART exposure in utero or postpartum was associated with persistent decreases in lymphocytes, neutrophils and platelets as well as an increased risk of transient lactic acidaemia, anaemia and mitochondrial DNA depletion, although these laboratory findings were generally not associated with clinical symptoms. We conclude that large, prospective studies of HIV-exposed infants are needed to resolve the discrepant results regarding morbidity and mortality related to mitochondrial disorders, to ascertain the clinical significance of effects on laboratory values, to determine whether or not the incidence of mitochondrial disorders differs by regimen and to develop predictive models that might identify which infants are at the greatest risk. The challenges that remain to be addressed include the development of a sensitive but affordable screening algorithm in combination with specific diagnostic criteria; consistent collection of data on ART exposure and other risk factors, long-term follow-up of HIV-exposed but uninfected children and implementation in resource-limited settings.
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PMID:Mitochondrial disorders among infants exposed to HIV and antiretroviral therapy. 1786 23

Effective gene therapy for haemophilia A necessitates a vector system that is not subject to a pre-existing immune response, has adequate coding capacity, gives long-term expression and preferably can target non-dividing cells. Vector systems based on lentiviruses such as equine infectious anaemia virus (EIAV) fulfil these criteria for the delivery of factor VIII (FVIII). We have found that B domain-deleted (BDD) FVIII protein inhibits functional viral particle production when co-expressed with the EIAV vector system. Although particle numbers (as measured by reverse transcriptase activity) are near normal, RNA genome levels are reduced and measurement of integrated copies revealed the virus is severely defective in its ability to transduce target cells. This is due to the absence of sufficient vesicular stomatitis virus glycoprotein (VSV-G) envelope on viral particles derived from cells expressing FVIII. By using an internal tissue-specific promoter, that has low activity in the producer cells, to drive expression of FVIII we have overcome this inhibitory effect allowing us to generate titres approaching those obtained with vector genomes encoding reporter genes. Furthermore, we report that codon optimization of the full-length FVIII gene increased vector titres approximately 10-fold in addition to substantially improving expression per integrated vector copy.
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PMID:Analysis of factor VIII mediated suppression of lentiviral vector titres. 1804 28


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