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)

The development of new antiviral strategies for the treatment of chronic hepatitis B remains a major goal since hepatitis virus (HBV) is resistant to interferon treatment as well as to new nucleoside analogs. HBV is a small DNA virus that replicates its genome via a reverse transcription step. The viral polymerase has been the main viral target that was studied to design new antiviral treatments. Active research has led to the discovery of new nucleoside analogs that are potent inhibitors of the viral reverse transcriptase. Among them, lamivudine has also proven antiviral efficacy in clinical trials with a sustained inhibition of viral replication. However, due to the kinetics of viral clearance, long-term antiviral therapy is necessary to eradicate viral infection. These prolonged regimens are associated with the emergence of drug-resistant strains that harbor mutations in the viral polymerase gene within the conserved B and C domains. New approaches using combinations of nucleoside analogs or other strategies, such as immune intervention (DNA vaccine, stimulation of the TH1 response ) or gene therapy (antisense oligonucleotides, dominant negative mutants), should therefore be evaluated in animal models to optimize the current antiviral protocols.
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PMID:New antiviral agents for the therapy of chronic hepatitis B virus infection. 1051 67

We investigated changes in the titers of positive and negative strands of hepatitis G virus (HGV) RNA and hepatitis C virus (HCV) RNA in serum and liver during and 1 to 3 years after interferon therapy in patients with chronic hepatitis C coinfected with HGV/ GBV-C. Eight (6%) of 134 patients with chronic hepatitis C treated with interferon were positive for HGV RNA and were examined retrospectively. Titers of positive and negative strands of HGV RNA and HCV RNA were determined by strand-specific reverse transcriptase-polymerase chain reaction. Before therapy, HGV RNA titers in liver were lower than those in serum (P = 0.0169), while HCV RNA titers in liver were significantly higher than those in serum (P = 0.0074). No negative strands of HGV RNA were detected in serum, liver, or peripheral blood mononuclear cells in any patients. With interferon therapy, 5 of the 8 patients lost HCV RNA from serum and liver, with sustained normal liver biochemical values and significant histological improvement. HGV RNA disappeared transiently from serum and liver at the end of therapy in 5 patients, but reappeared again after therapy in 4 of them. Two of the 8 patients naturally lost HGV RNA after completion of therapy. These findings suggest that: (1) HGV/GBV-C does not appear to replicate in liver, serum, or peripheral blood mononuclear cells, (2) detection of HGV RNA in liver and peripheral blood mononuclear cells may be a mere reflection of serum HGV RNA, and (3) the long-term clinical outcome of chronic HGV/GBV-C infection appeared to be benign.
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PMID:Long-term follow-up of hepatitis G virus/GB virus C replication in liver during and after interferon therapy in patients coinfected with hepatitis C and G viruses. 1058 92

Hepatitis B virus (HBV) infection is a worldwide public health problem. In France, 150,000 individuals are infected with the HBV. Although many are asymptomatic carriers, about 30% have chronic hepatitis, a condition associated with a risk of cirrhosis and hepatocellular carcinoma. Antiviral treatments, most notably interferon alpha, probably modify the natural history of hepatitis B, decreasing the risk of hepatocellular carcinoma and increasing survival. Nucleoside analogs, particularly lamivudine, have also demonstrated potent antiviral activity, which should however be weighed against the increasing risk over time of mutation development in the YMDD region of the DNA polymerase reverse transcriptase. Antiviral therapy monitoring should include clinical safety evaluations and periodic laboratory tests including blood cell counts, transaminase activities, and serum DNA levels. The improving results provided by antiviral drugs should not deflect attention away from the importance of large-scale hepatitis B immunization of neonates, which has been shown to decrease the incidence of hepatocellular carcinoma in areas with high levels of hepatitis B endemicity.
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PMID:[Hepatitis B: epidemiology, natural history, biology, treatment monitoring]. 1060 72

Generally, 0.4-2.5% of patients with chronic hepatitis C virus (HCV) infection develop hepatocellular carcinoma (HCC). HCC occurs more often in patients with cirrhosis and in those with increased liver cell proliferation. HCV-related tumors occur in older patients and often have a less aggressive course than HCC, related to other etiological factors. Many HCV-related HCC are multifocal in origin. However, many tumors grow as a single hepatic nodule for years before generating satellite or distant tumor nodules. The growth pattern varies from one tumor to another, with tumor volume doubling times ranging from 1 to 20 months. Tumor progression and hepatic failure are the leading causes of death in most patients. Using the polymerase chain reaction technique, HCV-RNA has been almost invariably detected in serum and tumor tissue of anti-HCV patients with HCC. In many patients, HCV-RNA was found to belong to the possibly more pathogenic type 1b. However, it is unlikely that HCV plays a direct role in liver tumorogenesis, since no reverse transcriptase activity has been found in infected livers. One current opinion is that HCV may promote cancer through cirrhosis, which is per se an important risk factor for this tumor. In HCV carriers, the risk of developing HCC and having more severe tumor disease may be increased by coexisting hepatitis B virus (HBV) or alcohol abuse, further supporting the idea that both HCC and cirrhosis might be a result of the interplay of several risk factors. HCC could also be the consequence of HCV interacting with cellular genes that regulate cell growth and differentiation, independent of the effect of cirrhosis.
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PMID:Natural history and pathogenesis of hepatitis C virus related hepatocellular carcinoma. 1062 56

Thirty-nine patients with chronic liver disease who were being evaluated in a U.S. military treatment facility were tested for antibody to hepatitis C virus (anti-HCV) and for hepatitis G virus (HGV) RNA by reverse transcriptase-polymerase chain reaction. Serum samples from 20 patients (51%) were positive for anti-HCV by immunoblot assay. HGV RNA was found in the sera of only two patients, both of whom were also positive for anti-HCV. HGV appears to have a limited role in causing chronic liver disease in this population of military patients, many of whom had traveled outside the United States. However, HCV infection was commonly associated with chronic hepatitis and cirrhosis, as in civilian patients.
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PMID:Chronic liver disease among U.S. military patients: the role of hepatitis C and G virus infection. 1074 Oct 77

After orthotopic liver transplantation (OLT), patients with chronic hepatitis C virus (HCV) infection show nearly universal persistence of viremia and reinfection of the liver, but identifying the point at which the liver is reinfected morphologically can be difficult. One tool that may potentially be useful to detect reinfection is reverse transcriptase-polymerase chain reaction (RT-PCR), which has proven to be highly sensitive for detecting HCV RNA in formalin-fixed paraffin-embedded liver tissue. Our purpose was to gain insight into the time frame of HCV reinfection by assaying for HCV RNA in serial posttransplant liver biopsy specimens. Our study population consisted of 14 patients who underwent liver transplantation for hepatitis C and had confirmed HCV RNA in pretransplant serum, absence of HCV RNA in donor livers, and available consecutive posttransplant liver allograft specimens. We performed RT-PCR for HCV RNA in serial posttransplant liver biopsy specimens, beginning at 1 week until at least one biopsy from each tested positive. HCV RNA was detected in liver tissue by RT-PCR in 1-week post-OLT liver samples in 6 of 14 (42.8%) patients, the earliest being 5 days post-OLT. Eventually, each of the remaining eight samples became RT-PCR positive as well; the first detections occurred in these at 3 weeks (three cases), 4 weeks (three cases), 48 weeks (one case), and 144 weeks (one case). Histologic identification of hepatitis C recurrence was relatively insensitive in relation to these molecular data. These data suggest that (1) HCV RNA reinfection is nearly universal after liver transplantation in patients with chronic hepatitis C infection, (2) molecular reinfection by HCV occurs at a variable interval post-OLT, with the majority of allograft livers reinfected as early as 1 week, and (3) morphologic features of hepatitis C are usually appreciable at the time of "molecular" recurrence.
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PMID:Early detection of hepatitis C allograft reinfection after orthotopic liver transplantation: a molecular and histologic study. 1075 33

The therapeutic goals in chronic hepatitis B are to prevent or decrease cirrhosis and hepatocellular carcinoma in patients with pre-cirrhotic or early cirrhotic disease and to stabilise patients with end-stage cirrhosis. Lamivudine is an oral nucleoside analogue that suppresses hepatitis B virus (HBV) replication, and so may achieve both these treatment objectives. The active 5'-triphosphate metabolite of lamivudine has two modes of viral suppression. First, it mimics deoxycytidine triphosphate and is incorporated into newly synthesised HBV DNA to cause chain termination. Second, it demonstrates competitive inhibition of viral DNA-dependent and RNA-dependent DNA polymerase activity (i.e., reverse transcriptase activity). Lamivudine may, therefore, act at four possible stages during HBV replication: reverse transcription of pre-genomic mRNA into nascent minus-strand DNA; formation of plus strand DNA from nascent minus-strand DNA; completion of double-stranded DNA; and formation of covalently closed circular DNA. In clinical studies, lamivudine therapy reduced serum HBV DNA and this was associated with significant improvements in liver histology and significant and sustained enhancement of the proliferative CD4-mediated response to HBeAg and hepatitis B core antigen (HBcAg), and an increased frequency of HBeAg-specific T cells. HBV DNA concentrations often returned to pre-treatment values when therapy ended prior to the loss of hepatitis B e antigen (HBeAg). Although the emergence of HBV variants with a mutation in the YMDD (tyrosine-methionine-aspartate-aspartate) motif has been observed, such variants show reduced susceptibility to lamivudine due to limited replication competence, and their emergence is not a signal to cease lamivudine therapy. In conclusion, viral suppression with lamivudine offers a means of disease improvement and immunological control in chronic hepatitis B.
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PMID:Profound suppression of hepatitis B virus replication with lamivudine. 1086 48

Several first-generation nucleoside analogues have been tested against chronic hepatitis B virus (HBV) infection, but trials were unsuccessful or accompanied by toxicity. Recently, oral second-generation nucleoside analogues have been developed that have potent activity against HBV. The best-studied compound so far is lamivudine ((-)2'-deoxy-3'-thiacytidine; 3TC). Lamivudine is an inhibitor of reverse transcriptase (RT) activity and is in clinical use in human immunodeficiency virus (HIV)-infected individuals. As several studies on the use of lamivudine for hepatitis B show, the development of resistance in the viral polymerase under lamivudine treatment, however, causes a significant clinical problem. All other drugs in advanced clinical development for HBV are nucleosides; cross-resistance is therefore expected in most cases. The history of HIV treatment demonstrates that new classes of drugs, the protease inhibitors and non-nucleosidic inhibitors of RT, allowed for a longer-term clinical benefit when used in combination with nucleoside analogues. The development of non-nucleosidic compounds with different modes of action therefore appears very important for the treatment of chronic hepatitis B as well.
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PMID:Development of resistance and perspectives for future therapies against hepatitis B infections: lessons to be learned from HIV. 1088 29

Hepatitis B virus has been known to frequently undergo mutations of its genome at various sites, mostly due to it employing a reverse transcriptase devoid of proofreading capacity in the course of its replication. The purpose of the present study has been to screen 257 HBsAg-positive chronic liver disease patients, more specifically 78 cases chosen at random out of those negative for HBeAg and 33 of the HBeAg-positive cases serving as controls for three discreet point mutations in the precore/core region of hepatitis B virus. To that end, HBV DNA extracted from sera was amplified by polymerase chain reaction (PCR) using semi-nested primers and subsequently subjected to restriction fragment length polymorphism (RFLP) analysis, 36 HBeAg-negative versus 30 HBeAg-positive sera, respectively, as well as to direct sequencing in some samples randomly selected to corroborate the RFLP results. Our results showed double mutations at positions 1762 and 1764 of the core promoter in between 25/36 (69.4%) and 19/25 (76%) of the sera tested, a missense mutation of the start codon in between 8/36 (22.2%), and 5/25 (20%) and a mutation turning codon 1896 into a stop codon in between 9/36 (25%) and 6/25 (24%) determined by RFLP and sequencing, respectively. These data indicate the double mutation at positions 1762 and 1764 to be the most prevalent among HBeAg-negative chronic hepatitis patients in Thailand whereas, in contrast to reports from other Asian countries, the mutation at nucleotide 1896 occurred in a mere 25%, while on the other hand the mutation abolishing the start of protein synthesis was observed to occur at a higher frequency than determined in several other geographical areas.
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PMID:Prevalence of core promotor and precore mutants of hepatitis B virus in thailand by RFLP and sequencing. 1092 70

In the present study, we demonstrated that a close relationship exists between hepatitis C virus (HCV) infection of peripheral blood mononuclear cells (PBMCs) and cell-surface Fas expression in patients with hepatitis C, and showed the possibility of PBMCs apoptosis via a Fas-mediated system. The expression of Fas on PBMCs was found by flowcytometric analysis to be significantly increased in these patients. In addition, the treatment of patients' PBMCs with anti-Fas antibody induced cell death, with nuclear condensation and fragmentation and cellular DNA fragmentation. These data indicate that the patients' PBMCs expressed a large amount of functional Fas on the cell surface and were susceptible to stimulation against Fas, causing apoptotic cell death. We then quantified the serum-soluble Fas ligand (sFasL), which was known to bind to Fas and induce the apoptotic signals into the sensitized cells. The patients' serum sFasL levels were significantly higher than those of normal subjects and showed a good negative correlation with their PBMC number. To demonstrate the correlation between Fas expression and HCV infection, nested reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect HCV RNA. Interestingly, HCV RNA was preferentially detected from Fas-positive cells but not from Fas-negative cells, which had been isolated from PBMCs by magnetic beads. These results suggest that HCV infection of PBMCs might induce Fas expression and additional stimulation such as sFasL might induce apoptosis in these Fas-expressing cells. These mechanisms, in addition to hypersplenism, may explain the decrease in the number of PBMCs observed in patients with chronic hepatitis C.
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PMID:Fas-mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C. 1093 Sep 83


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