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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Worldwide, HCV is a major etiologic agent of chronic hepatitis that may lead to the development of liver cirrhosis and hepatocellular carcinoma. Thus, significant morbidity and mortality is caused by HCV infection and effective control measures against the spread of this virus are needed. Originally, the extent of genetic heterogeneity of HCV was not fully appreciated. However, the breadth of the genetic heterogeneity of HCV is great, and this may have important implications in diagnosis, pathogenesis, treatment, and vaccine development. In an infected individual the HCV genome population circulates as a quasispecies distribution of closely related yet heterogeneous RNA sequences centered around one dominant sequence. The dominant sequence, as well as the consensus sequence, changes sequentially during the course of the infection. A hypervariable region (HVR1) within one of the envelope proteins of HCV (E2) evolves very rapidly. Patients infected with HCV mount a humoral immune response to epitopes of HVR1. However, sequential changes in the consensus sequence of HVR1 during infection result in the generation of variants that are not recognized by preexisting antibodies. This might represent a mechanism by which HCV evades host immune surveillance and establishes and maintains persistent infection. It will be important to determine whether HVR1 of HCV, as was found for the V3 loop of HIV, contains epitopes that elicit neutralizing antibodies against HCV. Furthermore, it will be important to determine whether the quasispecies nature of HCV helps the virus evade the cytotoxic T-cell response of the host. Analysis of complete or partial HCV genomic sequences revealed that HCV exists as multiple, distinct genotypes. A total of nine major genetic groups and at least 30 subgroups have been recognized. To evaluate the current classification of HCV genotypes, we performed phylogenetic analyses of complete and partial nucleotide sequences from isolates that represent all published variants of HCV. Analysis of complete HCV sequences, which represent three major genetic groups, supports the currently used genotype classification scheme. However, analysis of the partial genomic regions (ie, C, E1, and NS5b) of HCV isolates that represent all recognized variants of HCV demonstrates that the genetic relatedness among some of the genotypes was not equivalent in the different gene regions. Furthermore, the distinction among isolates, subtypes, and types of HCV was not always clear. This finding might reflect the shortcomings of analyzing only limited gene regions or may reflect the wide spectrum of genetic variation of HCV.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. 759 43

Hepatitis C virus (HCV) infection is associated with a wide spectrum of liver diseases including cirrhosis and hepatocellular carcinoma (HCC). Although the biological relation between the virus and cirrhosis or HCC is unclear, such variable pathogenicity may be related to the genetic heterogeneity of HCV. Genetic variability of HCV was assessed by determining the nucleotide sequence corresponding to the hypervariable regions (HVR1 and HVR2) of the putative envelope protein (E2/NS1) in positive- and negative-stranded HCV RNA from the cancerous and surrounding non-cancerous liver tissue, peripheral blood mononuclear cells and serum of a patient with HCC. Nineteen distinct HVR1 amino acid sequences (deduced from the nucleotide sequences) were obtained from the patient and could be classified into 5 groups on the basis of the site and time of detection. Some viral isolates with the same HVR1 sequence were shown to replicate in both cancerous and non-cancerous liver tissue, whereas others replicated in HCC tissue only.
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PMID:Comparison of hypervariable regions (HVR1 and HVR2) in positive- and negative-stranded hepatitis C virus RNA in cancerous and non-cancerous liver tissue, peripheral blood mononuclear cells and serum from a patient with hepatocellular carcinoma. 876 May 88

Hepatitis C virus (HCV) is an important etiological agent in the development of chronic liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The virus, identified only recently, contains a single-stranded RNA genome of positive polarity, is distantly related to pestiviruses and flaviviruses, and has been classified as the first member of a third genus within the family Flaviviridae. Extensive analysis of HCV genomic sequences demonstrated that this virus possesses significant genetic heterogeneity. Different regions of the viral genome demonstrate a varying degree of heterogeneity; the regions coding for the putative envelope proteins are the most variable sites between different isolates. Furthermore, HCV circulates as a quasispecies in the host. During the course of acute and chronic infection, the sequence composition of the HCV population in one patient has been found to change sequentially with an extremely high rate of nonconserved nucleotide changes in the hypervariable region I (HVR1) of HCV. Such sequence changes alter the antigenicity of the epitopes coded within HVR1 so that these are not always recognized by preexisting antibodies. It has been suggested that this could represent one mechanism by which HCV evades host immune surveillance and may account for the high rate of chronicity observed in such infections. Continuous viral replication may, in turn, lead to the development of chronic liver disease, including HCC, in infected individuals. To date, at least nine major genetic groups (genotypes 1-9) and more than 30 subgroups of HCV have been recognized based on genetic differences. A distinct difference has been observed in the genotype distribution in Africa compared with other continents. Recent data have suggested a difference in pathogenesis and in the outcome of interferon therapy in individuals infected with HCV of certain genotypes. For example, genotype 1b (II) seems to be associated with more severe liver disease, including HCC, and with a poorer response to interferon therapy. The extensive genetic heterogeneity of HCV may have serious implications for the diagnosis, treatment and prevention of hepatitis C as well as in understanding the biology of infection by this important human pathogen.
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PMID:Genetic heterogeneity of the hepatitis C virus. 887 12

To investigate the potential clinical utility of antibody response to HVR1 of HCV, the genomic and amino acid diversity of HVR1 was compared between two groups of four chronic HCV carriers with or without liver cirrhosis. Peptides corresponding to the deduced COOH- and NH2-terminal amino acid sequences of HVR1 were synthesised to assess the reactivity of patient sera to autologous and homologous HVR1 epitopes by enzyme-linked immunosorbent assay. HCV chronic carriers had significantly more frequent cross-reactivity with homologous C- than N-terminal HVR1 peptides. Twelve cirrhotic and eleven noncirrhotic patients had a similar frequency of cross-reactivity with either C- or N-terminal HVR1 peptides. However, noncirrhotic patients had a significantly higher level of C-terminal HVR1 antibody cross-reactivity than cirrhotic patients. In HCV chronic carriers, the magnitude of the immune response to but not the frequency of cross-reactivity with C-terminus HVR1 peptides differ between patients with and without liver cirrhosis.
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PMID:Hypervariable region diversity of hepatitis C virus and humoral response: comparison between patients with or without cirrhosis. 1044 Aug 4

The hepatitis C virus (HCV) is an RNA virus that replicates with a high rate of mutation, especially in the hypervariable region 1 (HVR-1). Continuous viral mutations lead to a mixed and changing populations of mutants, called quasispecies. The nature of the HCV quasispecies may have implications for viral persistence and pathogenies. Studies with liver transplant patients suggest a relationship between the degree of immunosuppression and the complexity of the quasispecies. This study evaluated whether immunosuppressive therapy modifies the evolution of HCV quasispecies among liver transplant recipients compared with immunocompetent HCV patients. Two groups were studied: 11 patients who underwent OLT for HCV-related cirrhosis and 10 control group patients. Two serum samples from each patient were obtained to analyze the HCV HVR1 region by RT-PCR. SSCP analysis failed to show statistically significant differences in the number of quasispecies at basal and final time points or at pretransplant versus posttransplant (7.3+/-2 vs 6.7+/-3 in control patients, respectively, and 4.4+/-2 vs 4.1+/-1 in transplanted patients, respectively). No significant difference was observed between missing or new variants in the control (2.8+/-2 vs 2.3+/-2, respectively) or transplanted group (2.5+/-2 vs 2.2+/-1, respectively). Upon sequence analysis, the genetic complexity was significantly lower among samples after OLT in transplanted patients (0.057+/-0.04 [pretransplant] vs 0.035+/-0.02 [posttransplant]; P=.048). However, no significant differences were found among control patients in basal versus final samples (0.04+/-0.03 vs 0.066+/-0.04, respectively). Our findings seem to demonstrate that viral quasispecies diversity is lower among patients receiving a liver transplant.
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PMID:Analysis of hepatitis C viral quasispecies in liver transplantation. 1296 16

Hepacivirus A (also known as nonprimate hepacivirus and equine hepacivirus) is a hepatotropic virus that can cause both transient and persistent infections in horses. The evolution of intrahost viral populations (quasispecies) has not been studied in detail for hepacivirus A, and its roles in immune evasion and persistence are unknown. To address these knowledge gaps, we first evaluated the envelope gene (E1 and E2) diversity of two different hepacivirus A strains (WSU and CU) in longitudinal blood samples from experimentally infected adult horses, juvenile horses (foals), and foals with severe combined immunodeficiency (SCID). Persistent infection with the WSU strain was associated with significantly greater quasispecies diversity than that observed in horses who spontaneously cleared infection (P = 0.0002) or in SCID foals (P < 0.0001). In contrast, the CU strain was able to persist despite significantly lower (P < 0.0001) and relatively static envelope diversity. These findings indicate that envelope diversity is a poor predictor of hepacivirus A infection outcomes and could be dependent on strain-specific factors. Next, entropy analysis was performed on all E1/E2 genes entered into GenBank. This analysis defined three novel hypervariable regions (HVRs) in E2, at residues 391 to 402 (HVR1), 450 to 461 (HVR2), and 550 to 562 (HVR3). For the experimentally infected horses, entropy analysis focusing on the HVRs demonstrated that these regions were under increased selective pressure during persistent infection. Increased diversity in the HVRs was also temporally associated with seroconversion in some horses, suggesting that these regions may be targets of neutralizing antibody and may play a role in immune evasion.IMPORTANCE Hepacivirus C (hepatitis C virus) is estimated to infect 150 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. In contrast, its closest relative, hepacivirus A, causes relatively mild disease in horses and is frequently cleared. The relationship between quasispecies evolution and infection outcome has not been explored for hepacivirus A. To address this knowledge gap, we examined envelope gene diversity in horses with resolving and persistent infections. Interestingly, two strain-specific patterns of quasispecies diversity emerged. Persistence of the WSU strain was associated with increased quasispecies diversity and the accumulation of amino acid changes within three novel hypervariable regions following seroconversion. These findings provided evidence that envelope gene mutation is influenced by adaptive immune pressure and may contribute to hepacivirus persistence. However, the CU strain persisted despite relative evolutionary stasis, suggesting that some hepacivirus strains may use alternative mechanisms to persist in the host.
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PMID:Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome. 3329 93