Current management of HCV infection is based on Direct-Acting Antiviral Drugs (DAAs). However, resistance-associated mutations, especially in the NS3 and NS5B regions are gradually decreasing the efficacy of DAAs. Among the most effective HCV NS3/4A protease drugs, Sofosbuvir also develops resistance due to mutations in the NS3 and NS5B regions. Four mutations at positions A156Y, L36P, Q41H, and Q80K are classified as high-level resistance mutations. The resistance mechanism of HCV NS3/4A protease toward Sofosbuvir caused by these mutations is still unclear, as there is less information available regarding the structural and functional effects of the mutations against Sofosbuvir. In this work, we combined molecular dynamics simulation, molecular mechanics/Generalized-Born surface area calculation, principal component analysis, and free energy landscape analysis to explore the resistance mechanism of HCV NS3/4A protease due to these mutations, as well as compare interaction changes in wild-type. Subsequently, we identified that the mutant form of HCV NS3/4A protease affects the activity of Sofosbuvir. In this study, the resistance mechanism of Sofosbuvir at the atomic level is proposed. The proposed drug-resistance mechanism will provide valuable guidance for the design of HCV drugs.

HCV is a hepatotropic RNA virus recognized for its frequent virulence and fatality worldwide. Despite many vaccine development programs underway, researchers are on a quest for natural bioactive compounds due to their multivalent efficiencies against viral infections, considering which the current research aimed to figure out the target-specificity and therapeutic potentiality of α, β, and δ subunits of amyrin, as novel bioactive components against the HCV influx mechanism. Initially, the novelty of amyrin subunits was conducted from 203 pharmacophores, comparing their in-silico pharmacokinetic and pharmacodynamic profiles. Besides, the best active site of CD81 was determined following the quantum tunneling algorithm. The molecular dynamic simulation was conducted (100 ns) following the molecular docking steps to reveal the parameters- RMSD (Å); Cα; RMSF (Å); MolSA (Å2); Rg (nm); PSA (Å); SASA (Å2), and the MM-GBSA dG binding scores. Besides, molecular strings of CD81, along with the co-expressed genes, were classified, as responsible for encoding CD81-mediated protein clusters during HCV infection, resulting in the potentiality of amyrins as targeted prophylactics in HCV infection. Finally, in vivo profiling of the oxidative stress marker, liver-specific enzymes, and antioxidant markers was conducted in the DMN-induced mice model, where β-amyrin scored the most significant values in all aspects.

Hepatitis C virus (HCV) is a positive-stranded RNA virus causing chronic liver diseases. The chemical modification of RNA is a research hotspot in related fields in recent years, including the methylation and acetylation of adenine, guanine, cytosine and other bases, among which methylation is the most important modification form. m6A (N6-methyladenosine), as the most abundant RNA modification form, plays an important role in HCV virus infection by modifying viral RNA and cell transcripts. This review aims to summarize the current knowledge on the roles of m6A modification in HCV infection, and discuss the research prospect.

Hepatitis C virus (HCV) infection was the primary reason causing critical hepatic Q7 diseases. Although direct-acting antiviral agents (DAA) were widely used in clinics, anti-drug mutation, the outcome of patients with different viral subtypes, and recurrence suggested that HCV pathogenic mechanism should be studied further. HCV infection, replication, and outcome were influenced by the IFNL4 and itsdownstream genes (MxA and MxB). However, whether genetic polymorphisms of these genes played necessary roles required verification in the Yunnan population.
After analyzing the genotypes and allele frequencies of seven single nucleotide polymorphisms (SNP), we found the association between the genotype and allele frequencies of rs11322783 in the IFNL4 gene and HCV infection in Yunnan population. Furthermore, the genetic polymorphisms of the MxA and MxB genescould influence liver function of HCV patients. The indirect bilirubin (IBIL) and albumin (ALB) levels showed significant differences among HCV patients, who carried various genotypes. The IBIL levels were associated with genotypes of rs17000900 (P= 0.025) and rs2071430 (P= 0.037) in the MxA gene, and ALB levels were associated with genotypes of rs2838029 (P= 0.010) in the MxB gene. Similarly, the genotypes of SNPs also showed significant difference in patients infected with subtype 3a (P=0.035) and 2a (P=0.034). However, no association was identified between expression level and SNPs of the MxA and MxB genes. Furthermore, HCV subtype 3b was found to be the predominantly epidemic strain in Yunnan Province.
In conclusion, the association between biochemical indices/HCV subtypes and SNPs in the MxA and MxB genes was identified in Yunnan HCV population.

Hepatitis C virus (HCV) infection is a major public health concern, and almost two million people are infected per year globally. This is occurred by the diverse spectrum of viral genotypes, which are directly associated with chronic liver disease (fibrosis, and cirrhosis). Indeed, the viral genome encodes three principal proteins as sequentially core, E1, and E2. Both E1 and E2 proteins play a crucial role in the attachment of the host system, but E2 plays a more fundamental role in attachment. The researchers have found the \"E2-CD81 complex\" at the entry site, and therefore, CD81 is the key receptor for HCV entrance in both humans, and chimpanzees. So, the researchers are trying to block the host CD81 receptor and halt the virus entry within the cellular system via plant-derived compounds. Perhaps that is why the current research protocol is designed to perform an in silico analysis of the flavonoid compounds for targeting the tetraspanin CD81 receptor of hepatocytes. To find out the best flavonoid compounds from our library, web-based tools (Swiss ADME, pKCSM), as well as computerized tools like the PyRx, PyMOL, BIOVIA Discovery Studio Visualizer, Ligplot+ V2.2, and YASARA were employed. For molecular docking studies, the flavonoid compounds docked with the targeted CD81 protein, and herein, the best-outperformed compounds are Taxifolin, Myricetin, Puerarin, Quercetin, and (-)-Epicatechin, and outstanding binding affinities are sequentially - 7.5, - 7.9, - 8.2, - 8.4, and - 8.5 kcal/mol, respectively. These compounds have possessed more interactions with the targeted protein. To validate the post docking data, we analyzed both 100 ns molecular dynamic simulation, and MM-PBSA via the YASARA simulator, and finally finds the more significant outcomes. It is concluded that in the future, these compounds may become one of the most important alternative antiviral agents in the fight against HCV infection. It is suggested that further in vivo, and in vitro research studies should be done to support the conclusions of this in silico research workflow.

OBJECTIVE: Although the pathogenesis of hepatocellular carcinoma (HCC) is still unclear, hepatitis C virus (HCV) infection is considered a common cause of HCC. It has been reported that DDX60L can inhibit HCV replication, but its role in HCC is still poorly understood.
METHODS: The expression levels of DDX60L in HCC tissues and in tissues adjacent to the tumor and their correlation with the clinicopathological features of patients were analyzed. We also used Kaplan-Meier curves of overall survival (OS) with Cox regression analysis and log-rank test to investigate the prognostic value of DDX60L in HCC. We further performed cell proliferation, Transwell, and wound healing assays to elucidate the role of DDX60L in HCC using the siRNA-DDX60L Hep3B or HCCLM3 cell line.
RESULTS: Univariate analysis showed that sex, Edmondson grade, microvascular invasion, tumor stage (III-IV/I-II), AFP, and DDX60L expression were strongly associated with the prognosis of HCC patients. The results of multivariate analysis further suggested that DDX60L might be an independent prognostic factor for OS in patients with HCC (P moderate/low = 0.015, P high/low = 0.011). The low DDX60L expression in HCC patients with no-metastasis, age ≥55 years, tumor size <5 cm, Edmondson grade = I-II, microvascular invasion, no cirrhosis, HBV positivity, tumor stage = III-IV, AFP >20 μg/L, and multiple tumor was associated with poorer prognosis (P <0.05). Moreover, the expression of DDX60L was significantly lower in HCC samples (N = 285) than in the normal tissues adjacent to the tumor (N = 167, P <0.001). There were no HCV-related HCC patients in this study. Additionally, we found that DDX60L knockdown can promote the proliferation of Hep3B cells, migration and invasion ability of Hep3B and HCCLM3 cells.
CONCLUSIONS: We found that the downregulation of DDX60L expression correlated with poor prognosis in patients with HCC, which may be independent of the HCV-related pathway. Furthermore, DDX60L significantly inhibited the proliferation of Hep3B cells, migration and invasion of Hep3B and HCCLM3 cells. Therefore, DDX60L can serve as a prognostic biomarker and therapeutic target for HCC.

BACKGROUND: Previous studies have reported that hepatitis C virus infection may increase the risk of thyroid disease and even thyroid cancer, but quantitative assessments of risk were rare and the results were not consistent. The purpose of this study was to evaluate the impact of hepatitis C virus infection on thyroid disease and thyroid cancer, and to provide clues to explore their relationship.
METHODS: A literature retrieval was performed up to August 20, 2021 in the database of PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wang Fang. The risk of hepatitis C virus for thyroid disease or thyroid cancer was expressed with odds ratio (OR) and 95% confidence intervals (CI). Subgroup analysis was used to explore the source of heterogeneity. Eight articles (Five studies published as articles and three as abstracts) were included in this meta-analysis, with a total of 5398 controls and 1925 cases of hepatitis C.
RESULTS: The results of a meta-analysis found that hepatitis C virus infection was significantly associated with an increased risk of thyroid disease (sum OR = 1.80, 95% CI = 1.54-2.10, P < 0.001, I2 = 74.3%) and thyroid cancer (sum OR = 16.74, 95% CI = 4.78-58.55, P < 0.001, I2 = 0%). Hepatitis C virus infection may increase the risk of thyroid disease and thyroid cancer.
CONCLUSIONS: More work is needed in the future to establish a causal role; however, an awareness of the possibility of increased risk of thyroid disease and thyroid cancer may lead to earlier diagnosis and better outcomes in patients with hepatitis C.

BACKGROUND: Increasing evidence suggests that hepatitis C virus (HCV) infection is associated with non-Hodgkin\'s lymphoma (NHL). However, no clear consensus has been reached about the clinical features and effective treatment of HCV-associated NHL patients. We therefore performed a systematic review and meta-analysis to explore the clinical characteristics and effectiveness of antiviral treatment or rituximab administration among NHL patients with HCV infection.
METHODS: Eight electronic databases, including PubMed, OVID, EMBASE, Cochrane Library, ClinicalTrials, WANFANG, CNKI, and VIP, were searched for eligible studies up to July 31, 2021. The hazard ratio (HR) or odds ratio (OR) corresponding to the 95% confidence interval (CI) was calculated to estimate the outcomes. Publication bias was assessed by Egger\'s and Begg\'s tests. Statistical analysis was performed with RevMan 5.4 software and Stata version 15.
RESULTS: There were 27 shortlisted articles out of a total of 13,368 NHL patients included in the current meta-analysis. Our results demonstrated that NHL patients with HCV infection had a significantly shorter overall survival (OS: HR 1.89; 95% CI 1.42-2.51, P < 0.0001) and progression-free survival (PFS: HR 1.58; 95% CI 1.26-1.98, P < 0.0001), a lower overall response rate (ORR: OR 0.58, 95% CI 0.46-0.73, P < 0.00001) and a higher incidence of hepatic dysfunction during chemotherapy (OR 5.96; 95% CI 2.61-13.62, P < 0.0001) than NHL patients without HCV infection. HCV-positive NHL patients exhibited an advanced disease stage, an elevated level of LDH, a high-intermediate and high IPI/FLIPI risk as well as a higher incidence of spleen and liver involvement. Moreover, antiviral treatment prolonged survival (OS: HR 0.38; 95% CI 0.24-0.60, P < 0.0001), reduced disease progression [PFS/DFS (disease-free survival): HR 0.63; 95% CI 0.46-0.86, P = 0.003] and reinforced the treatment response (ORR: OR 2.62; 95% CI 1.34-5.11, P = 0.005) among the HCV-infected NHL patients. Finally, rituximab administration was associated with a favourable OS, while liver cirrhosis and low levels of albumin predicted a poor OS for HCV-positive NHL patients.
CONCLUSIONS: The current study provided compelling evidence about an inferior prognosis and distinct clinical characteristics among HCV-associated NHL patients. Antiviral treatment and rituximab-containing regimens were shown to be efficacious in improving the clinical outcomes of NHL patients with HCV infection.

UNASSIGNED: Ras-related nuclear (RAN) protein is a small GTP-binding protein that is indispensable for the translocation of RNA and proteins through the nuclear pore complex. Recent studies have indicated that RAN plays an important role in virus infection. However, the role of RAN in hepatitis C virus (HCV) infection is unclear. The objective of this study was to investigate the role and underlying mechanisms of RAN in HCV infection.
UNASSIGNED: Huh7.5.1 cells were infected with the JC1-Luc virus for 24 h and then were incubated with complete medium for an additional 48 h. HCV infection and RAN expression were determined using luciferase assay, quantitative reverse transcription-PCR and western blotting. Small interfering RNA was used to silence RAN. Western blotting and immunofluorescence were used to evaluate the cytoplasmic translocation of polypyrimidine tract-binding (PTB), and coimmunoprecipitation was used to examine the interaction between RAN and PTB.
UNASSIGNED: HCV infection significantly induced RAN expression and cytoplasmic redistribution of PTB. Knockdown of RAN dramatically inhibited HCV infection and the cytoplasmic accumulation of PTB. Colocalization of RAN and PTB was determined by immunofluorescence, and a direct interaction of RAN with PTB was demonstrated by coimmunoprecipitation.
UNASSIGNED: PTB in the host cytoplasm is directly associated with HCV replication. These findings demonstrate that the involvement of RAN in HCV infection is mediated by influencing the cytoplasmic translocation of PTB.

暂无摘要。