Does the hepatitis C virus replicate in cells of the hematopoietic lineage?

Negro, Francesco; Levrero, Massimo

doi:10.1002/hep.510280134

Cited by 17 publications

(10 citation statements)

References 73 publications

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“…The presence of extrahepatic sites of HCV replication is now established and based on several lines of evidence, [20][21][22][23][24] even though in some specific settings, the level of extrahepatic replication of HCV seems to be low-level. 25,26 Thus, we cannot exclude that the lack of correlation between intrahepatic minusstrand HCV-RNA titer and HCV viremia level may be a result, at least in part, of a significant contribution of the viral load from extrahepatic sites. In conclusion, we feel safer to assume that the detection of the minus-strand HCV RNA in a given tissue provides, at best, the evidence of the presence of HCV replication.…”

Section: Discussionmentioning

confidence: 98%

Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reversetranscriptase polymerase chain reaction

Negro

Krawczynski

Quadri³

et al. 1999

Hepatology

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Studies aimed at correlating the intrahepatic hepatitis C virus (HCV)-RNA level and anatomo-clinical features have been difficult because of sensitivity and specificity shortcomings of available techniques. We titered the genomic-and minus-strand HCV RNAs by a strand-specific, semiquantitative, genotype-independent reverse-transcriptase polymerase chain reaction (RT-PCR) in the liver tissue of 61 patients with chronic hepatitis C. Findings were correlated with the levels of HCV RNA in the serum, the HCV genotype, the expression of intrahepatic HCV antigens, the histological activity (using separate scores for the lobular and the portal/periportal necroinflammatory activity and for the fibrosis), and the response to interferon alfa (IFN-␣) treatment. Genomic-and minus-strand HCV RNA were detected in 59 and 57 liver specimens, respectively. The pathogenesis of the hepatitis C virus (HCV)-associated liver disease is believed to be mainly mediated by the immune system. 1 However, some studies have shown a direct correlation between the viremia level and the hepatitis activity, 2-6 thus suggesting a direct cytopathogenic effect of HCV on hepatocytes. Ideally, the correlation between HCV replicative levels and pathological findings (as well as with other clinical features) should rely on the quantitation of HCV RNA (or antigens) in the liver. Unfortunately, correlative studies between the semiquantitation of HCV replicative levels in the liver and the disease activity have been difficult because of the technical shortcomings of the published techniques. In particular, the detections of HCV RNA by commercially available (semi)quantitative assays have some limitations as to their sensitivity or variation coefficient, 7,8 and may amplify different viral genotypes with a different efficiency. 9 Moreover, all diagnostic assays are aimed at detecting the genomicstrand HCV RNA; therefore, they may also detect the virions' RNA trapped in the liver biopsy specimens at the time of sampling. On the other hand, the specificity of the detection of the minus-strand HCV RNA (the putative HCV replication intermediate RNA) has been repeatedly questioned. 10 Suitably modified reverse-transcriptase polymerase chain reaction (RT-PCR)-based assays of sufficient specificity are now available 10 and can be applied to the analysis of clinical specimens.We have previously detected the intrahepatic minus-strand HCV RNA by a semiquantitative, strand-specific RT-PCR in liver transplant recipients. 11 In that study, we showed a lack of correlation between the HCV-RNA level in the serum, the genomic-and the minus-strand HCV-RNA titers in the liver on the one hand, and the histological grading and staging of the liver disease on the other. 11 In the present work, we applied the same assay to a series of liver biopsy specimens taken from chronic hepatitis C patients. Our aim was to assess whether clinically significant correlations could be established between the intrahepatic titers of either strand of HCV RNA and some histopathological and clinica...

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Section: Discussionmentioning

confidence: 98%

Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reversetranscriptase polymerase chain reaction

Negro

Krawczynski

Quadri³

et al. 1999

Hepatology

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“…Controversial data on the actual ability of HCV to replicate in PBMC have been reported (17,21), suggesting a limited contribution of PBMC to the total HCV RNA burden. In addition, no clear-cut differences between the three groups of patients examined were observed.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of Serum and Liver Hepatitis C Virus RNA Levels in Patients Coinfected with Human Immunodeficiency Virus and Treated with Antiretroviral Drugs

Furione

Maserati²,

Gatti

et al. 2004

J Clin Microbiol

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We examined hepatitis C virus (HCV) RNA levels in serum, peripheral blood mononuclear cells (PBMC), and the liver for 135 patients with chronic HCV infections, 44 of whom were human immunodeficiency virus (HIV) positive and treated with highly active antiretroviral therapy (group A), 66 of whom were HIV negative (group B), with abnormal serum alanine aminotransferase (ALT) values, and 25 of whom were HIV negative, with ALT values of <1.5 times the normal value (group C). Patients had not been treated with interferon, with or without ribavirin, at the time of the study. A statistically significant correlation between HCV RNA levels in the liver and serum was reproducibly documented, whereas this was inconsistent for serum and PBMC. A comparative evaluation of HCV RNA levels in the liver and PBMC showed significantly lower values for group A than for groups B and C (P < 0.01 and P < 0.0001, respectively). In contrast, HCV RNA levels in serum were significantly higher for group A than for group B (P < 0.001). A dissociation between HCV RNA levels in serum and the liver was found for patients with HIV-HCV coinfections. Although the relative contribution of extrahepatic reservoirs, including lymphoid cells, to HCV RNA levels in serum is unclear, it may be speculated that a low intrahepatic HCV burden is caused by restored immunocompetence after successful antiretroviral therapy in coinfected patients.

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“…These studies produced conflicting findings, as a result of methodological problems, and only recently has a consensus begun to emerge that low-level replication occurs in some extrahepatic sites, particularly in the presence of immunosuppression (4,30,33,36,43). In contrast, other members of the Flaviviridae family display an overt, broad cellular tropism resulting in multifaceted disease expression (60).…”

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confidence: 99%

Identification of Unique Hepatitis C Virus Quasispecies in the Central Nervous System and Comparative Analysis of Internal Translational Efficiency of Brain, Liver, and Serum Variants

Forton

Karayiannis

Mahmud

et al. 2004

J Virol

225

171

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Reports of cerebral dysfunction in chronic hepatitis C virus (HCV) infection have led to the suggestion that HCV may infect the central nervous system (CNS). We used reverse transcription-PCR, cloning, and sequencing to define quasispecies for the HCV internal ribosomal entry site (IRES) and hypervariable region 1 (HVR1) in autopsy-derived brain, liver, lymph node, and serum samples. There was evidence of tissue compartmentalization of sequences in the brain in two patients, with between 24 and 55% of brain-derived IRES sequences absent from the serum, and significant phylogenetic and phenetic clustering of the brain and lymph node HVR1 sequences. The IRES initiates cap-independent translation of the viral polyprotein. Two unique brain-derived IRES mutations (C 204 3A and G 243 3A), which have previously been associated with lymphoid replication and altered translational efficiency in cell culture, were found in one patient. We used a dicistronic reporter vector to test whether brain-derived variants showed altered IRES-mediated translational efficiency, which might favor CNS infection. The translational efficiencies of the brain-derived IRES sequences were generally reduced compared to those of the master serum and liver sequences in rabbit reticulocyte cell lysates and two human cell lines, HuH7 (liver) and CHME3 (microglial). The C 204 3A and G 243 3A mutations showed preserved translational efficiency in HuH7 cells but reduced efficiency in CHME3 cells. Our data provide evidence that the CNS is a site of HCV replication, consistent with the recent demonstration of negative-strand HCV RNA in brain, and suggest that IRES polymorphisms may be important as a viral strategy of reduced translation to favor latency in the CNS.

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Does the hepatitis C virus replicate in cells of the hematopoietic lineage?

Abstract: [No abstract available

Cited by 17 publications

References 73 publications

Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reversetranscriptase polymerase chain reaction

Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reversetranscriptase polymerase chain reaction

Dissociation of Serum and Liver Hepatitis C Virus RNA Levels in Patients Coinfected with Human Immunodeficiency Virus and Treated with Antiretroviral Drugs

Identification of Unique Hepatitis C Virus Quasispecies in the Central Nervous System and Comparative Analysis of Internal Translational Efficiency of Brain, Liver, and Serum Variants

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