Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aetiological agent of chronic hepatitis C is the hepatitis C virus. The hepatitis C virus is spread by parenteral transmission of body fluids, primarily blood or blood products. In 1989, after more than a decade of research, HCV was isolated and characterised. The hepatitis C viral genome is a positive-sense, single-stranded RNA molecule approximately 9.4 kb in length, which encodes a polyprotein of about 3100 amino acids. There are 6 main genotypes of HCV, each further stratified by subtype. In 1994, a cohort of women was identified in Ireland as having been iatrogenically exposed to the hepatitis C virus. The women were all young and exposed as a consequence of the receipt of HCV 1b contaminated anti-D immunoglobulin. The source of the infection was identified as an acutely infected female. As part of a voluntary serological screening programme involving 62,667 people, 704 individuals were identified as seropositive for exposure to the hepatitis C virus; 55.4% were found to be positive for the viral genome 17 years after exposure. Of these women 98% had evidence of inflammation, but surprisingly, a remarkable 49% showed no evidence of fibrosis. Clinicopathology and virological analysis has identified associations between viral load and the histological activity index for inflammation, and, between inflammation and levels of the liver enzyme alanine aminotransferase. Infection at a younger age appears to protect individuals from progression to advanced liver disease. Molecular analyses of host immunogenetic elements shows that particular class II human leukocyte associated antigen alleles are associated with clearance of the hepatitis C virus. Additional class II alleles have been identified that are associated with stable viraemia over an extended period of patient follow-up. Although, investigation of large untreated homogeneous cohorts is likely to become more difficult, as the efficacy of anti-viral therapy improves, further investigation of host and viral factors that influence disease progression will help provide an evidence based approach were realistic expectations regarding patient prognosis can be ascertained.
Int J Mol Med 2002 Feb
PMID:The Irish paradigm on the natural progression of hepatitis C virus infection: an investigation in a homogeneous patient population infected with HCV 1b (review). 1178 30

Hepatitis C virus (HCV) has been linked to extrahepatic manifestations such as oral lichen planus (OLP). In addition, anticardiolipin antibodies (aCL) and cryoglobulin have been demonstrated in chronic hepatitis C. The aim of this study was to investigate these prevalences in patients with HCV-associated OLP. The prospective study investigated the role of these factors in 133 subjects: 28 with OLP-HCV(+) (group 1), 22 with OLP-HCV(-) (group 2), 33 without OLP-HCV(+) (group 3), and 50 healthy volunteers matched for age and sex served as control group (group 4). Levels of immunoglobulin G (IgG) and IgM aCL antibodies, and cryoglobulin in serum were evaluated by enzyme-linked immunosorbent assay. The prevalence of aCL in groups 1, 2, 3, and 4 were 32.1, 18, 36.3, and 8%, respectively. The positive rate of aCL was significantly higher in groups 1 and 3 than that in the control group (group 1; p=0.02 vs. the control group, group 3; p<0.01 vs. the control group). There were no significant differences in cryoglobulin among the groups. The findings of the present study showed a high prevalence of IgG and IgM aCL in the serum of patients with HCV infectious diseases. A positive factor for aCL was determined by age, sex, the presence of OLP, and HCV infection.
Int J Mol Med 2002 Mar
PMID:High prevalence of anticardiolipin antibodies in patients with HCV-associated oral lichen planus. 1183 36

The NS3 protein of the hepatitis C virus (HCV) is a 631 amino acid residue bifunctional enzyme with a serine protease localized to the N-terminal 181 residues and an RNA helicase located in the C-terminal 450 residues. The HCV NS3 RNA helicase consists of three well-defined subdomains which all contribute to its helicase activity. The second subdomain of the HCV helicase is flexibly linked to the remainder of the NS3 protein and could undergo rigid-body movements during the unwinding of double-stranded RNA. It also contains several motifs that are implicated in RNA binding and in coupling NTP hydrolysis to nucleic acid unwinding and translocation. As part of our efforts to use NMR techniques to assist in deciphering the enzyme's structure-function relationships and developing specific small molecule inhibitors, we have determined the solution structure of an engineered subdomain 2 of the NS3 RNA helicase of HCV, d(2Delta)-HCVh, and studied the backbone dynamics of this protein by (15)N-relaxation experiments using a model-free approach. The NMR studies on this 142-residue construct reveal that overall subdomain 2 of the HCV helicase is globular and well structured in solution even in the absence of the remaining parts of the NS3 protein. Its solution structure is very similar to the corresponding parts in the X-ray structures of the HCV NS3 helicase domain and intact bifunctional HCV NS3 protein. Slow hydrogen-deuterium exchange rates map to a well-structured, stable hydrophobic core region away from the subdomain interfaces. In contrast, the regions facing the subdomain interfaces in the HCV NS3 helicase domain are less well structured in d(2Delta)-HCVh, show fast hydrogen-deuterium exchange rates, and the analysis of the dynamic properties of d(2Delta)-HCVh reveals that these regions of the protein show distinct dynamical features. In particular, residues in motif V, which may be involved in transducing allosteric effects of nucleotide binding and hydrolysis on RNA binding, exhibit slow conformational exchange on the milli- to microsecond time-scale. The intrinsic conformational flexibility of this loop region may facilitate conformational changes required for helicase function.
J Mol Biol 2001 Nov 30
PMID:Solution structure and backbone dynamics of an engineered arginine-rich subdomain 2 of the hepatitis C virus NS3 RNA helicase. 1184 66

In this study the authors applied a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect hepatitis C virus (HCV) RNA in 15 frozen liver biopsy samples from anti-D-treated patients. They also correlated the presence or absence of HCV RNA in the serum and liver of each patient with their histologic gradings. RNA was extracted from 36 frozen liver biopsy samples. These included 15 liver biopsy samples from patients infected with HCV through contamination of anti-D blood products. Three of these 15 anti-D-treated patients were receiving alpha-interferon treatment at the time of liver biopsy. Nine frozen liver biopsy samples from patients with a history of intravenous drug abuse were included as positive controls. HCV-negative frozen liver biopsy samples from 12 noninfected patients were used as negative controls. RNA was also extracted from six frozen skin biopsy specimens to check for cross-contamination of samples. Eleven of 15 anti-D-treated patients were HCV RNA positive by RT-PCR, with 100% correlation between HCV RNA in the serum and liver. The nine frozen liver biopsy samples from the intravenous drug abuse patients (positive controls) were also RT-PCR positive for HCV RNA. The 12 noninfected samples and the negative control biopsy samples were negative for HCV. Twenty-seven percent of the recombinant immunoblot assay-positive patients were serum and liver HCV RNA negative. HCV-positive patients receiving alpha-interferon therapy at the time of biopsy had cleared the virus from the serum and the liver. There was no correlation between the presence or absence of serum and liver HCV RNA with the histologic grading. This lack of correlation shows clearly the importance of histopathologic evaluation of liver biopsy samples in monitoring HCV-associated liver disease progression. In addition, this finding indicates that one cannot rely only on the presence or absence of HCV RNA in either serum or liver tissue as a parameter in monitoring HCV-associated liver disease progression in this unique cohort of anti-D-treated patients.
Diagn Mol Pathol 2002 Mar
PMID:Lack of association between hepatitis C viral RNA in serum and liver and histologic gradings: a study on Irish anti-D-treated patients. 1185 99

Early diagnosis of hepatitis C infection and early identification of virologic response to antiviral therapy represent major hallmarks of the quality of a case. They contribute to reducing the risk of hepatitis C infection from blood product and improve disease management in patients treated with antivirals. Some of the current issues and perspectives involved in detection and quantification of viral load during the incubation phase of infection and monitoring the early phase of antiviral therapy are discussed.
Expert Rev Mol Diagn 2001 Sep
PMID:Hepatitis C virus infection: early diagnosis and identification of response to antiviral therapy. 1190 36

Ribavirin, an antiviral drug discovered in 1972, is interesting and important for three reasons: (a) it exhibits antiviral activity against a broad range of RNA viruses; (b) it is currently used clinically to treat hepatitis C virus infections, respiratory syncytial virus infections, and Lassa fever virus infections; and (c) ribavirin's mechanism of action has remained unclear for many years. Here we recount the history of ribavirin and review recent reports regarding ribavirin's mechanism of action, including our studies demonstrating that ribavirin is an RNA virus mutagen and ribavirin's primary antiviral mechanism of action against a model RNA virus is via lethal mutagenesis of the RNA virus genomes. Implications for the development of improved versions of ribavirin and for the development of novel antiviral drugs are discussed.
J Mol Med (Berl) 2002 Feb
PMID:Ribavirin's antiviral mechanism of action: lethal mutagenesis? 1190 45

Autoimmunity and high rates of autoantibodies have been implicated in the pathogenesis of porphyria cutanea tarda. These abnormalities could be in part virus-induced, since porphyria cutanea tarda in most geographical regions is highly associated with hepatitis C virus infection. We analyzed the link of autoantibodies, autoimmune hepatitis and systemic lupus erythematosus in 111 patients with porphyria cutanea tarda and sex- and age-matched controls (mean age 58+/-13 years) in Germany, a region with a low prevalence of hepatitis C virus infection. Patients with porphyria cutanea tarda displayed lower rates of anti-nuclear antibodies (16/111, 14% vs 28/111, 25%, p<0,05) and of antibodies against smooth muscle (25/111, 23% vs 48/111, 43%, p<0,01), than controls. The percentage of patients with porphyria cutanea tarda with positive anti-HCV was low but significantly higher than in our controls (9/111, 8% vs 0/111, 0%, respectively), (p<0,05). Two patients with porphyria cutanea tarda (2/111, 2%) fulfilled the criteria for systemic lupus erythematosus and not one of 65 patients was found to have clinical autoimmune hepatitis. In the first controlled study of a large cohort of patients with porphyria cutanea tarda no increased prevalence of selected autoantibodies and autoimmune hepatitis was found. However, a higher prevalence of HCV infection and systemic lupus erythematosus in patients with porphyria cutanea tarda was confirmed.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Autoimmunity and HCV infection in porphyria cutanea tarda: a controlled study. 1192 46

The purpose of this study was to localize HCV RNA in formalin-fixed paraffin-embedded liver biopsies of 15 patients with chronic hepatitis C using in situ RT-PCR method. The results were compared to serum and tissue extract analysis of HCV RNA. HCV RNA was detected in 80% of the sera tested, in 40% of the corresponding hepatic tissue extract and in 60% of the tissue sections tested by in situ RT-PCR. Compared to the serum positive cases, 67% of the cases were positive with in situ RT-PCR and 41% were positive with tissue extract detection. 50% of the cases in situ RT-PCR positive were also positive with tissue extract detection. These results underlined the complementarity of the different methods of viral detection for the precise diagnosis of hepatitis C.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:Hepatitis C virus RNA detection by in situ RT-PCR in formalin-fixed paraffin-embedded liver tissue. Comparison with serum and tissue results. 1193 64

To determine whether the persistent nature of hepatitis C infection is related to the emergence of antigenic variants driven by immune selection, we examined the sequence heterogeneity in a portion of the hepatitis C virus (HCV) nonstructural 3 (NS3) gene of a patient infected over the course of more than 2 years. By PCR amplification, cloning, and sequencing, we observed several variable and conserved regions in the NS3 segment of the HCV genome. All variable regions had higher ratios of nonsynonymous/synonymous mutations and encompassed immunodominant epitopes, and their locations were not essential to maintain the known function of HCV RNA helicase. In contrast, the regions that are critical for HCV RNA helicase activity were found to be conserved with lower heterogeneity or lower ratios of nonsynonymous/synonymous mutations, and none except one of these regions was encoded within immunodominant epitopes. Our results are consistent with immune selection of viral variants at the epitope and molecular levels that may enable HCV to evade host defenses over time. Plotting the relatedness of sequence variants revealed a star topology suggesting that a wild-type HCV sequence is maintained, unlike HIV.
J Mol Evol 2002 Apr
PMID:Sequence variation in the gene encoding the nonstructural 3 protein of hepatitis C virus: evidence for immune selection. 1195 85

Hepatitis C virus (HCV) is an RNA virus infecting 1 in every 40 people worldwide. Development of new therapeutics for treating HCV has been hampered by the lack of small-animal models. We have adapted existing hydrodynamic transfection methods to optimize the delivery of RNAs to the cytoplasm of mouse liver cells in vivo. Transfected HCV genomic RNA failed to replicate in mouse liver, suggesting a post-entry block to viral replication. Real-time imaging of HCV internal ribosome entry site (IRES) firefly luciferase reporter mRNA translation in living mice demonstrated that the HCV IRES was functional in mouse liver. We then used this system as a model for studying HCV RNA translation in mice. We compared translation by several mutant HCV IRES variants in cell lysates, cultured cells, and mouse liver. We measured the contribution to translation of a cap, HCV 3'-untranslated region (UTR), poly(A) tail, domains II, IIIb, IIIabc, IIIabcd, IIId, and the initiator codon. Efficient translation required a 3'-UTR in mice and HeLa cells, but not in rabbit reticulocyte lysates. Translational regulation of transfected RNAs was stringent in mice. The method we describe could be useful for studies in mice of antisense or ribozyme inhibitors targeting the IRES as well as other RNA biochemical studies in vivo.
Mol Ther 2002 Jun
PMID:Determinants of hepatitis C translational initiation in vitro, in cultured cells and mice. 1202 51


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