Serum HCV RNA titer does not predict the severity of liver damage in HCV carriers with normal aminotransferase levels

Puoti, Claudio; Stati, Tonino; Magrini, Andrea

doi:10.1111/j.1478-3231.1999.tb00018.x

Cited by 50 publications

(27 citation statements)

References 62 publications

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“…Hence, the model suggests that there is no obvious correlation between pathology and virus load. This is consistent with clinical data (de Araujo et al, 2002;Manzin et al, 1997;Pontisso et al, 1999;Puoti et al, 1999).…”

Section: Discussionsupporting

confidence: 91%

Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses

Wodarz

2003

Journal of General Virology

160

111

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This paper investigates the role of CTL and antibody responses in hepatitis C virus (HCV) dynamics and pathology. Mathematical models suggest that a strong CTL response is required for resolution of HCV infection and that a weak CTL response can result in persistent infection. According to the model, establishment of persistent infection is accompanied mainly by an ongoing antibody response, while CTLs are not maintained at high levels. In the model, this outcome correlates with absence of pathology. Persistent infection in the face of an ongoing antibody response can result in evolution of antigenic escape. According to the model, evolution towards escape from antibodies can shift the balance of immune responses so that the weak CTL levels become increasingly more dominant relative to antibodies. This shift results in onset of liver pathology as the virus evolves towards increased levels of antigenic escape. Therefore, the relative balance of the immune response can be a decisive factor that determines whether patients are asymptomatic or whether pathology is observed. Virus evolution can shift this balance towards pathology over time. Theoretical results are discussed in the context of published data.

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Section: Discussionsupporting

confidence: 91%

Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses

Wodarz

2003

Journal of General Virology

160

111

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“…These data demonstrate a relationship between HCV replication and endogenous cobalamin concentration. To our knowledge, no correlation has been demonstrated between HCV viral load and any other measurable parameter (34). In our study, neither HCV viral load nor total serum cobalamin concentration correlated with alanine aminotransferase (ALT) levels (data not shown), in agreement with a recent report (35).…”

Section: Specificity Of Inhibition For the Hcv Ires Bicistronic Conssupporting

confidence: 92%

Vitamin B12 and hepatitis C: Molecular biology and human pathology

Lott

Takyar

Tuppen

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Cobalamins are stored in high concentrations in the human liver and thus are available to participate in the regulation of hepatotropic virus functions. We show that cyanocobalamin (vitamin B12) inhibited the HCV internal ribosome entry site (IRES)-dependent translation of a reporter gene in vitro in a dose-dependent manner without significantly affecting the cap-dependent mechanism. Vitamin B12 failed to inhibit translation by IRES elements from encephalomyocarditis virus (EMCV) or classical swine fever virus (CSFV). We also demonstrate a relationship between the total cobalamin concentration in human sera and HCV viral load (a measure of viral replication in the host). The mean viral load was two orders of magnitude greater when the serum cobalamin concentration was above 200 pM (P < 0.003), suggesting that the total cobalamin concentration in an HCV-infected liver is biologically significant in HCV replication.T he hepatitis C virus (HCV) is an important human pathogen, infecting about 1% of the global population. Approximately 30% of chronically infected carriers develop serious liver disease, making it the single leading indicator for liver transplantation (1). HCV is believed to be noncytopathic, and hepatocellular injury likely results from an abortive immune response to virus-infected cells. During HCV infection, HCV RNA replicates by using a virally encoded RNA-dependent RNA polymerase without a DNA intermediate (2). Because the virion presumably contains only the positive-strand genomic RNA and the virally encoded structural proteins, translation of the HCV genome to produce the viral proteins required for replication is an early obligatory step in the replication cycle. Translation initiates in the 5Ј untranslated region (UTR) and proceeds 5Ј to 3Ј along the positive strand genomic RNA, whereas transcription to synthesize the negative-strand RNA is thought to initiate in the 3Ј UTR of the positive strand and proceeds from 3Ј to 5Ј. It is unlikely that the transcription complex (replicase) of a positive-strand RNA virus can compete with actively translating ribosomal subunits for the same RNA template (3-5). Therefore, HCV should down-regulate its own translation to achieve initiation of transcription. Such regulatory mechanisms probably affect initiation, rather than elongation, thus allowing the translation machinery to clear the template (4). The virus can use a virally encoded protein or cellular factor as a regulatory agent, targeting the HCV internal ribosome entry site (IRES) (6). It is reasonable to suggest that a highly tissue-specific virus like HCV may evolve to use a compound in which that tissue is rich for such a regulatory purpose.HCV initiates translation by a mechanism that is distinct from the usual eukaryotic cap-dependent mechanism (7). Antiviral drug design targeting this mechanism has been proposed (8, 9), because it may yield a therapy with high viral specificity and low host cellular toxicity. The putative regulatory mechanism outlined above suggests that partial inhibition of H...

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“…However, studies on the correlations between HCV RNA titers or HCV genotype, and the severity of liver damage have shown conflicting results (13)(14)(15)(16)(17). In addition, whether HCV RNA titer is a better predictor of underlying liver injury than serum ALT is not known.…”

Section: Introductionmentioning

confidence: 99%

The Relationship of Histologic Activity to Serum ALT, HCV genotype and HCV RNA titers in Chronic Hepatitis C

et al. 2001

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It is unclear whether serum ALT levels or virological characteristics of hepatitis C virus(HCV) including HCV genotypes and HCV RNA titers, can reflect the degree of histological injury in chronic hepatitis C. The aim of this study was to investigate the relationships between the levels of histological damage and serum ALT levels, HCV genotypes or circulating HCV RNA titers in chronic hepatitis C. A total of 56 patients underwent liver biopsy and the histological activity index (HAI) was evaluated by Knodell's scoring system. HCV genotype by RT-nested PCR and HCV RNA quantitation by competitive RT-PCR were performed. Thirty-four patients were infected with HCV genotype 1b, 20 patients with genotype 2a, and 2 patients with undetermined type. Serum ALT levels were not positively correlated with total HAI score or HCV RNA titers, but showed a linear correlation with scores of piecemeal necrosis (r=0.32, p<0.05) and portal inflammation (r=0.27, p<0.05). HCV genotype had no significant correlation with RNA titers, HAI score or with serum ALT levels. Also, no statistical relationship was seen between HCV RNA titer and HAI score. These results suggest that liver histology is essential to evaluate the severity of chronic hepatitis C precisely.

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Serum HCV RNA titer does not predict the severity of liver damage in HCV carriers with normal aminotransferase levels

Cited by 50 publications

References 62 publications

Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses

Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses

Vitamin B12 and hepatitis C: Molecular biology and human pathology

The Relationship of Histologic Activity to Serum ALT, HCV genotype and HCV RNA titers in Chronic Hepatitis C

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