Hepatitis C virus genotypes and the development of hepatocellular carcinoma

Stankovic-Djordjevic, Dobrila; Djordjevic, N.; Tasić, Gordana; Dinić, Marina; Karanikolić, Aleksandar; Pešić, Milica

doi:10.1111/j.1443-9573.2007.00282.x

Cited by 10 publications

(8 citation statements)

References 48 publications

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“…The results clearly demonstrate a correlation between genotype-specific internal cleavage activity and transforming activity of NS3. They also suggest a possible contribution of the internal NS3 cleavage to the significant differences in clinical severity for patients infected with different HCV genotypes (26,34,42). The minor increase of the transforming activity of NS3(JFH-1) in the presence of NS4A may result from the function of NS4A in stabilizing the NS3 protein.…”

Section: Resultsmentioning

confidence: 98%

Differential Requirements of NS4A for Internal NS3 Cleavage and Polyprotein Processing of Hepatitis C Virus

Kou¹,

Chang

Wang³

et al. 2007

J Virol

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The NS3 protein of hepatitis C virus (HCV) possesses protease activity responsible for the proteolytic cleavage of the viral polyprotein at the junctions of nonstructural proteins downstream of NS3. The NS3 protein was also found to be internally cleaved. In this study, we demonstrated that internal cleavages occurred on the NS3 protein of genotype 1b in the presence of NS4A, both in culture cells and with a mouse model system. No internal cleavage products were detected with the NS3 and NS4A proteins of genotype 2a. Three potential cleavage sites were detected in the NS3 protein (genotype 1b), with IPT 402 ͦS being the major one. The internal cleavage requires the polyprotein processing activity of NS3 protease, but when supplemented in trans, the internal cleavage efficiency is reduced. In addition, several mutations in NS4A disrupted the internal cleavage of NS3 but did not affect polyprotein processing, indicating that NS4A contributes differently to these two proteolytic activities. Furthermore, Ile-25, Val-26, and Ile-29 of the NS4A protein, important for the NS4A-dependent internal cleavages, were also shown to be critical for the transforming activity of NS3, but mutations at these critical residues resulted only in a slight increase of HCV replicating efficiency. The internal cleavage-associated enhancement of the transforming activity of NS3 was reduced when a T402A substitution at the major internal cleavage site was introduced. The multiple roles of NS4A in viral multiplication and pathogenesis make NS4A an ideal molecular target for HCV therapy.Hepatitis C virus (HCV) is a member of the family Flaviviridae with a single-stranded, positive-sense RNA of 9.6 kb that encodes a polyprotein of approximately 3,000 amino acid residues (8,18,35). The polyprotein precursor is further processed into structural and nonstructural proteins by cellular signal peptidase and viral proteases. Cleavage at the NS2-NS3 junction occurs autoproteolytically with the NS2-3 protease (15), whereas cleavage of the downstream nonstructural proteins is mediated by the viral NS3 serine protease (3,10,14).The viral NS3 protein has multiple functions. The Nterminal-one-third region possesses protease activity, and the C-terminal-two-thirds region contains NTPase and RNA helicase activities. In addition, previous studies indicate that the N-terminal domain of the NS3 protein has the potential for cell transformation (30,41,43). Subcutaneous inoculation of nude mice with cells previously transfected with a plasmid that expresses a C-terminal deletion NS3 protein induced tumor formation (16). Mechanisms of NS3 involved in cell transformation are not fully understood. Nevertheless, the transforming ability of NS3 was abolished when cells were treated with the protease inhibitors phenylmethylsulfonyl fluoride and tosylsulfonyl phenylalanyl chloromethyl ketone (43). This indicates that protease activity is required for the transforming activity of the HCV NS3 protein. Furthermore, internal cleavages of the NS3 protein have been reported....

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Section: Resultsmentioning

confidence: 98%

Differential Requirements of NS4A for Internal NS3 Cleavage and Polyprotein Processing of Hepatitis C Virus

Kou¹,

Chang

Wang³

et al. 2007

J Virol

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“…The secretion of CTSB, like the secretion of matrix metalloproteases, is a marker of the progression of the proteolytic degradation of the extracellular matrix, which plays an important part in cancer invasion and metastasis. Since infection with HCV of genotype 1 is clinically considered a risk factor for the development of hepatocellular carcinoma (14,51), the enhanced secretion of pro-CTSB by the replication of genotype 1 strains might synergistically promote infiltration of hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, HCV infection is known to induce extrahepatic diseases such as type 2 diabetes and malignant lymphoma (20). It is believed that the frequency of development of these diseases varies among viral genotypes (14,51). However, the precise mechanism of the genotype-dependent outcome of HCV-related diseases has not yet been elucidated.…”

mentioning

confidence: 99%

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Taguwa¹,

Kambara²,

Fujita

et al. 2011

J Virol

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Hepatitis C virus (HCV) is a major cause of chronic liver diseases. A high risk of chronicity is the major concern of HCV infection, since chronic HCV infection often leads to liver cirrhosis and hepatocellular carcinoma. Infection with the HCV genotype 1 in particular is considered a clinical risk factor for the development of hepatocellular carcinoma, although the molecular mechanisms of the pathogenesis are largely unknown. Autophagy is involved in the degradation of cellular organelles and the elimination of invasive microorganisms. In addition, disruption of autophagy often leads to several protein deposition diseases. Although recent reports suggest that HCV exploits the autophagy pathway for viral propagation, the biological significance of the autophagy to the life cycle of HCV is still uncertain. Here, we show that replication of HCV RNA induces autophagy to inhibit cell death. Cells harboring an HCV replicon RNA of genotype 1b strain Con1 but not of genotype 2a strain JFH1 exhibited an incomplete acidification of the autolysosome due to a lysosomal defect, leading to the enhanced secretion of immature cathepsin B. The suppression of autophagy in the Con1 HCV replicon cells induced severe cytoplasmic vacuolation and cell death. These results suggest that HCV harnesses autophagy to circumvent the harmful vacuole formation and to maintain a persistent infection. These findings reveal a unique survival strategy of HCV and provide new insights into the genotype-specific pathogenicity of HCV.Hepatitis C virus (HCV) is a major causative agent of bloodborne hepatitis and currently infects at least 180 million people worldwide (58). The majority of individuals infected with HCV develop chronic hepatitis, which eventually leads to liver cirrhosis and hepatocellular carcinoma (25,48). In addition, HCV infection is known to induce extrahepatic diseases such as type 2 diabetes and malignant lymphoma (20). It is believed that the frequency of development of these diseases varies among viral genotypes (14, 51). However, the precise mechanism of the genotype-dependent outcome of HCV-related diseases has not yet been elucidated. Despite HCV's status as a major public health problem, the current therapy with pegylated interferon and ribavirin is effective in only around 50% of patients with genotype 1, which is the most common genotype worldwide, and no effective vaccines for HCV are available (35, 52). Although recently approved protease inhibitors for HCV exhibited a potent antiviral efficacy in patients with genotype 1 (36, 43), the emergence of drug-resistant mutants is a growing problem (16). Therefore, it is important to clarify the life cycle and pathogenesis of HCV for the development of more potent remedies for chronic hepatitis C.HCV belongs to the genus Hepacivirus of the family Flaviviridae and possesses a single positive-stranded RNA genome with a nucleotide length of 9.6 kb, which encodes a single polyprotein consisting of approximately 3,000 amino acids (40). The precursor polyprotein is processed by host...

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“…However, the question whether HCV genotype plays a role in the development of liver cirrhosis and HCC is still debatable. Previously, the effect of HCV genotype 1b has been scrutinized as a risk factor for HCC [25,26] . However, some other studies have revealed no preferential role of individual HCV genotypes in HCC [27,28] .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to these host factors, several viral factors such as genotype and peripheral viral load have also been reported to influence disease progression [24] . Some studies have identified that cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC compared to those infected with other HCV types [25,26] . However, the results of other studies [27,28] are in disagreement with these studies, and demonstrate no association of a particular HCV genotype with the development of HCC.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus genotype 3a infection and hepatocellular carcinoma: Pakistan experience

Idrees¹,

Rafique²,

Rehman³

et al. 2009

WJG

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AIM:To assess the association between chronic hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) in Pakistan, and the genotype distribution among these HCC patients. METHODS:One hundred and sixty-one subjects with HCC were included in this study. Liver biopsy was performed on 145 of the patients; sixteen were excluded because they failed to fulfill the inclusion criteria. Qualitative polymerase chain reaction (PCR) was performed for hepatitis B virus and HCV. Samples positive for HCV RNA were genotyped using genotypespecific PCR and confirmed by HCV 5' noncoding region sequencing analysis. RESULTS:Chronic HCV infection was identified a major risk factor (63.44% of tested HCC patients) for the development of HCC. The time from HCV infection to appearance of cancer was 10-50 years. In the HCC patient population, broader distributions of genotypes were present with genotype 3a as the predominant genotype. Using the type-specific genotyping method, we found HCV genotype 3a in 40.96%, 3b in 15.66%, 1a in 9.63%, and 1b in 2.40% of HCC tissue samples. About 28% of cases were found with mixed genotypes. Two cases were unable to be genotyped because of low viral load. Sixty-six percent of treated patients with cirrhosis had an end of treatment response, but unfortunately they relapsed quickly when the treatment was discontinued, and HCC developed during a median 3.8 years. CONCLUSION:There was a strong association between chronic HCV infection and HCC in Pakistan, and between HCV genotype 3a and HCC.

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Hepatitis C virus genotypes and the development of hepatocellular carcinoma

Cited by 10 publications

References 48 publications

Differential Requirements of NS4A for Internal NS3 Cleavage and Polyprotein Processing of Hepatitis C Virus

Differential Requirements of NS4A for Internal NS3 Cleavage and Polyprotein Processing of Hepatitis C Virus

Dysfunction of Autophagy Participates in Vacuole Formation and Cell Death in Cells Replicating Hepatitis C Virus

Hepatitis C virus genotype 3a infection and hepatocellular carcinoma: Pakistan experience

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