Differences in Hypervariable Region 1 Quasispecies of Hepatitis C Virus in Human Serum, Peripheral Blood Mononuclear Cells, and Liver

Okuda, Michiari; Hino, Keisuke; Korenaga, Masaaki; Yamaguchi, Yoshiyuki Y.; Katoh, Yoshiharu; Okita, Kiwamu

doi:10.1002/hep.510290117

Cited by 88 publications

(69 citation statements)

References 42 publications

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“…The concept of extrahepatic replication of HCV is not novel, with several lines of evidence suggesting that peripheral blood mononuclear cells are infected. [36][37][38][39] Microglia comprise up to 20% of all glial cells and are developmentally derived from bone marrow precursors of monocytic lineage. 40 It is believed that resident microglia turn over slowly and are replaced by circulating monocytes.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease

et al. 2002

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Patients with chronic hepatitis C virus (HCV) infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. Several studies have shown that patients exhibit low quality-of-life scores that are independent of disease severity. We therefore considered whether HCV infection has a direct effect on the central nervous system, resulting in cognitive and cerebral metabolite abnormalities. Twenty-seven viremic patients with biopsy-proven mild hepatitis due to HCV and 16 patients with cleared HCV were tested with a computer-based cognitive assessment battery and also completed depression, fatigue, and quality-of-life questionnaires. The HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group ( C hronic hepatitis C (HCV) infection is estimated to affect 170 million people worldwide 1 and constitutes a major public health problem. It causes a fluctuating chronic hepatitis that may progress to cirrhosis and hepatocellular carcinoma. Attempts to understand the natural history of this infection have largely focused on the viral and host factors that predict progression of liver pathology from necroinflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Consequently, the decision to treat patients is normally based on an assessment of these factors, including staging of disease with a liver biopsy, 2 rather than on particular symptoms. There is, however, emerging literature suggesting that, even in the absence of clinically significant liver disease, chronic HCV infection causes a substantial reduction in quality of life 3 that improves following successful antiviral treatment. 4 These findings are in agreement with the clinical observation that patients with chronic HCV infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. 5,6 The etiology of these symptoms is unknown. The symptoms do not appear to be associated with the degree of hepatitis, the presence of autoimmune disorders 5 or cirrhosis, 3 a history of intravenous drug usage (IVDU), 3 or the level of circulating cytokines. 7 We have previously reported cerebral metabolite abnormalities in patients with histologically proven mild HCV infection using proton magnetic resonance spectroscopy ( 1 H MRS). 8 These abnormalities are similar to the 1 H MRS changes reported in cerebral human immunodeficiency virus (HIV) infection in both cognitively impaired 9,10 and asymptomatic individuals. 11 In this study, we address the hypothesis that HCV infection can result in cerebral dysfunction, which may underlie both the neuropsychological symptoms and the 1 H MRS abnormalities described. We used a cognitive assessment battery to determine whether cognitive impairment exists in patients with histologically defined mild chronic HCV infection and 1 H MRS to determine whether cerebral metabolite abnormalities are associated with impaired cognitive function.

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Section: Discussionmentioning

confidence: 99%

Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease

et al. 2002

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“…In our previous work, we tried to explain the higher complexity in the liver by suggesting the existence of distinct functional compartments with different replication kinetics (5). Alternatively, since the final fate of sequences found in the replicating pool is unknown, the finding of highest complexity in the liver quasispecies might be explained by an excess contribution of sequences that will not be incorporated into mature virions and (34,37,49,54,57). Any extrahepatic contribution to the circulating pool should lead to the presence of readily obvious mixed populations in the serum.…”

Section: Discussionmentioning

confidence: 99%

“…Heterogeneous quasispecies in peripheral blood mononuclear cells (PBMC) of humans and in chimpanzees have been described (34,37,49,54,57), and it has been proposed that replication in this tissue might contribute to HCV serum quasispecies complexity. In the present study we have evaluated the implications of serum and liver quasispecies complexity in the natural course of the disease.…”

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confidence: 99%

Nucleotide and Amino Acid Complexity of Hepatitis C Virus Quasispecies in Serum and Liver

Cabot

Martell

Esteban

et al. 2000

J Virol

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The quasispecies nature of the hepatitis C virus (HCV) is thought to play a central role in maintaining and modulating viral replication. Several studies have tried to unravel, through the parameters that characterize HCV circulating quasispecies, prognostic markers of the disease. In a previous work we demonstrated that the parameters of circulating viral quasispecies do not always reflect those of the intrahepatic virus. Here, we have analyzed paired serum and liver quasispecies from 39 genotype 1b-infected patients with different degrees of liver damage, ranging from minimal changes to cirrhosis. Viral level was quantified by real-time reverse transcription-PCR, and viral heterogeneity was characterized through the cloning and sequencing of 540 HCV variants of a genomic fragment encompassing the E2-NS2 junction. Although in 95% of patients, serum and liver consensus HCV amino acid sequences were identical, quasispecies complexity varied considerably between the viruses isolated from each compartment. Patients with HCV quasispecies in serum more complex (26%) than, less complex (28%) than, or similarly complex (41%) to those in liver were found. Among the last, a significant correlation between fibrosis and all the parameters that measure the viral amino acid complexity was found. Correlation between fibrosis and serum viral load was found as well (R ‫؍‬ 0.7). With regard to the origin of the differences in quasispecies complexity between serum and liver populations, sequence analysis argued against extrahepatic replication as a quantitatively important contributing factor and supported the idea of a differential effect or different selective forces on the virus depending on whether it is circulating in serum or replicating in the liver. Flaviviridae (7,29,45). Its genome consists of a single-stranded RNA, with plus polarity, of 9,600 nucleotides, which does not integrate in the host genome, yet persistence is the rule. The damage caused during infection ranges from minimal changes to cirrhosis of the liver and hepatocarcinoma, but little is known about the mechanism of hepatocyte injury due to chronic infection. It seems very likely that the pathogenesis of HCV infection is directly related to a strong interplay between the host defense mechanisms and the virus's ability to evade them efficiently. Moreover, in order to persist, HCV must regulate its lytic potential and avoid elimination by the host immune system. Due to the quasispecies structure of the HCV viral population infecting single patients (39), the virus may use a variety of strategies to fulfill both requirements (11,17). Hepatitis C virus (HCV) is an enveloped virus classified in the familyThe dynamic component of the quasispecies structure is responsible for the rapid virus evolution (12). It works through a complex mixture of genomic sequences (quasispecies) which behaves as a single unit when facing changes in the environment. The genetic interaction within the viral population allows the system to distinguish the best possibility at any given...

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“…[79][80][81] While some of these data should be viewed cautiously, as a variety of techniques were utilized and a limited number of samples [82][83][84] Interestingly, sequence analysis has subsequently revealed that certain viral variants may be selected for growth in extrahepatic cell types, implying that HCV diversity directly impacts cell tropism. 85,86 Furthermore, several studies have described a non-random distribution of HCV sequences in hepatic and extrahepatic compartments, 72,[87][88][89][90][91][92][93][94][95][96] leading to the conclusion that the presence of tissue-specific sequences is compatible with independent viral replication in extrahepatic sites. It has also been speculated that HCV variants within distinct compartments may differ in their sensitivity to interferon, although this hypothesis has not been formally tested.…”

Section: Evidence For Extrahepatic Replication Of Hcvmentioning

confidence: 99%

Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences

2006

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Differences in Hypervariable Region 1 Quasispecies of Hepatitis C Virus in Human Serum, Peripheral Blood Mononuclear Cells, and Liver

Cited by 88 publications

References 42 publications

Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease

Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease

Nucleotide and Amino Acid Complexity of Hepatitis C Virus Quasispecies in Serum and Liver

Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences

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