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1.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204438

RESUMO

Hepatitis C virus (HCV) is associated with various liver diseases. Chronic HCV infection is characterized by an abnormal host immune response. Therefore, it is speculated that to suppress HCV, a well-regulated host immune response is necessary. 2-O-methylhonokiol was identified by the screening of anti-HCV compounds using Renilla luciferase assay in Huh 7.5/Con 1 genotype 1b replicon cells. Here, we investigated the mechanism by which 2-O-methylhonokiol treatment inhibits HCV replication using real-time PCR. Our data shows that treatment with 2-O-methylhonokiol activated innate immune responses via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway. Additionally, the immunoprecipitation result shows that treatment with 2-O-methylhonokiol augmented tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) by preventing p62 from binding to TRAF6, resulting in reduced autophagy caused by HCV. Finally, we reproduced our data with the conditioned media from 2-O-methylhonokiol-treated cells. These findings strongly suggest that 2-O-methylhonokiol enhances the host immune response and suppresses HCV replication via TRAF6-mediated NF-kB activation.


Assuntos
Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Interações Hospedeiro-Patógeno , NF-kappa B/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Replicação Viral , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular , Células Cultivadas , Hepatite C/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Modelos Biológicos , Estrutura Molecular
2.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069902

RESUMO

Hepatocellular carcinoma (HCC) still remains a difficult to cure malignancy. In recent years, the focus has shifted to lipid metabolism for the treatment of HCC. Very little is known about hepatitis B virus (HBV) and C virus (HCV)-related hepatic lipid disturbances in non-malignant and cancer tissues. The present study showed that triacylglycerol and cholesterol concentrations were similar in tumor adjacent HBV and HCV liver, and were not induced in the HCC tissues. Higher levels of free cholesterol, polyunsaturated phospholipids and diacylglycerol species were noted in non-tumorous HBV compared to HCV liver. Moreover, polyunsaturated phospholipids and diacylglycerols, and ceramides declined in tumors of HBV infected patients. All of these lipids remained unchanged in HCV-related HCC. In HCV tumors, polyunsaturated phosphatidylinositol levels were even induced. There were no associations of these lipid classes in non-tumor tissues with hepatic inflammation and fibrosis scores. Moreover, these lipids did not correlate with tumor grade or T-stage in HCC tissues. Lipid reprogramming of the three analysed HBV/HCV related tumors mostly resembled HBV-HCC. Indeed, lipid composition of non-tumorous HCV tissue, HCV tumors, HBV tumors and HBV/HCV tumors was highly similar. The tumor suppressor protein p53 regulates lipid metabolism. The p53 and p53S392 protein levels were induced in the tumors of HBV, HCV and double infected patients, and this was significant in HBV infection. Negative correlation of tumor p53 protein with free cholesterol indicates a role of p53 in cholesterol metabolism. In summary, the current study suggests that therapeutic strategies to target lipid metabolism in chronic viral hepatitis and associated cancers have to consider disease etiology.


Assuntos
Carcinoma Hepatocelular/metabolismo , Colesterol/metabolismo , Fígado/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Colesterol/fisiologia , Feminino , Alemanha/epidemiologia , Hepacivirus/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/metabolismo , Hepatite C/virologia , Humanos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade
3.
BMC Infect Dis ; 21(1): 413, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947337

RESUMO

BACKGROUND: The development of direct-acting antivirals (DAA) for HCV has revolutionized the treatment of HCV, including its treatment in patients with HIV coinfection. The aim of this study was to compare the changes in liver function between coinfected and monoinfected patients with cirrhosis who achieved HCV eradication by DAA. METHODS: Patients with pre-treatment diagnosis of HCV liver cirrhosis, consecutively enrolled in the multicenter PITER cohort, who achieved a sustained virological response 12 weeks after treatment cessation (SVR12) were analysed. Changes in Child-Pugh (C-P) class and the occurrence of a decompensating event was prospectively evaluated after the end of DAA treatment. Cox regression analysis was used to evaluate factors independently associated with changes in liver function following viral eradication. RESULTS: We evaluated 1350 patients, of whom 1242 HCV monoinfected (median follow-up 24.7, range 6.8-47.5 months after viral eradication) and 108 (8%) HCV/HIV coinfected (median follow-up 27.1, range 6.0-44.6). After adjusting for age, sex, HCV-genotype, HBsAg positivity and alcohol use, HIV was independently associated with a more advanced liver disease before treatment (C-P class B/C vs A) (OR: 3.73, 95% CI:2.00-6.98). Following HCV eradication, C-P class improved in 17/20 (85%) coinfected patients (from B to A and from C to B) and in 53/82 (64.6%) monoinfected patients (from B to A) (p = 0.08). C-P class worsened in 3/56 coinfected (5.3%) (from A to B) and in 84/1024 (8.2%) monoinfected patients (p = 0.45) (from A to B or C and from B to C). Baseline factors independently associated with C-P class worsening were male sex (HR = 2.00; 95% CI = 1.18-3.36), platelet count < 100,000/µl (HR = 1.75; 95% CI 1.08-2.85) and increased INR (HR = 2.41; 95% CI 1.51-3.84). Following viral eradication, in 7 of 15 coinfected (46.6%) and in 61 of 133 (45.8%) monoinfected patients with previous history of decompensation, a new decompensating event occurred. A first decompensating event was recorded in 4 of 93 (4.3%) coinfected and in 53 of 1109 (4.8%) monoinfected patients (p = 0.83). CONCLUSIONS: Improvement of liver function was observed following HCV eradication in the majority of patients with cirrhosis; however viral eradication did not always mean cure of liver disease in both monoinfected and coinfected patients with advanced liver disease.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Cirrose Hepática/virologia , Idoso , Coinfecção/tratamento farmacológico , Feminino , Infecções por HIV/tratamento farmacológico , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resposta Viral Sustentada , Resultado do Tratamento
4.
Viruses ; 13(4)2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916702

RESUMO

Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium-revealed by the changing composition of the mutant spectrum-may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed.


Assuntos
Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C/virologia , Antivirais/farmacologia , COVID-19 , Linhagem Celular , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Humanos , Mutação , RNA Viral , Ribavirina/farmacologia , Análise de Sequência , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacos
5.
Molecules ; 26(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802584

RESUMO

Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.


Assuntos
Antivirais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Desenvolvimento de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Antivirais/química , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Proliferação de Células , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Simulação de Acoplamento Molecular , Células Tumorais Cultivadas
6.
Medicine (Baltimore) ; 100(17): e25112, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907088

RESUMO

ABSTRACT: Alpha fetoprotein (AFP) level is the gold standard diagnostic tool for detection and monitoring hepatocellular carcinoma (HCC) but with low sensitivity. Thus, the identification of alternative or combined serum markers of HCC is highly needed. Therefore, the aim of this work was to verify the value of serum midkine (MDK), Dickkopf-related protein 1 (DKK1), and alpha-L-fucosidase (AFU) in detection of HCC.We recruited 244 subjects to the present study; 89 with liver cirrhosis, 86 cirrhotic hepatitis C virus (HCV) induced HCC, and 69 apparently healthy volunteers as controls. Serum AFP, MDK, DKK1, and AFU were measured by ELISA.Patients with HCC showed significantly higher serum MDK, DKK1, and AFU levels compared with those patients with liver cirrhosis and healthy controls (X2 = 179.56, 153.94, and 90.07 respectively) (P < .001 in all). In HCC cases, neither of MDK, DKK1, or AFU was correlated with tumor number. On the other hand, only serum DKK1 was significantly higher in lesions >5 cm, those with portal vein thrombosis and advanced HCC stage. Receiver operator characteristic (ROC) curve analysis showed that serum MDK levels discriminated between cirrhosis and HCC at a sensitivity of 100%, a specificity of 90% at cut-off value of >5.1 ng/mL.Although our results showed that serum MDK, DKK-1, and AFU are increased in HCC cases only MDK may be considered as the most promising serological marker for the prediction of the development of HCC in cirrhotic HCV patients.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Hepatite C/sangue , Cirrose Hepática/sangue , Neoplasias Hepáticas/diagnóstico , Midkina/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Hepacivirus , Hepatite C/complicações , Hepatite C/virologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Cirrose Hepática/complicações , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , alfa-L-Fucosidase/sangue
7.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809908

RESUMO

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-ß (TGF-ß) ligands. The endoglin/TGF-ß signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Suscetibilidade a Doenças , Endoglina/genética , Endoglina/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Endoglina/sangue , Endoglina/química , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/patologia , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Proteínas do Core Viral/metabolismo
8.
J Ayub Med Coll Abbottabad ; 33(1): 49-53, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33774954

RESUMO

BACKGROUND: Combination of DAAs, Sofosbuvir and Ribavirin has been known as an effective treatment for HCV genotype 3. The aim of our study is to assess the efficacy of Sofosbuvir and Ribavirin in relapsed HCV genotype 3 patients. METHODS: A cross-sectional retrospective analysis of hospital records between January 2015 and December 2016. Data was taken of only those patients who were followed for one year. A total of 193 cases were included in this study who were HCV genotype 3 relapsers and out of these 28 patients failed to be followed. Data was entered and analysed in IBM SPSS software package 23. RESULTS: Out of the total 193 cases, 74.1% of cases achieved RVR at 4 weeks of therapy. ETR was achieved by 91.2% cases, while 8.8% of cases were non-responders. There was statistical significance in gender achieving ETR with a p-value of .008. 84.5% of cases achieved SVR-12. Statistical significance was noted between haemoglobin levels at presentation and 4 weeks follow-up with a p-value <0.005, and also between 4 weeks and 12 weeks follow-up with a p-value <0.005. Statistical significance was also found between age and PCR at 4 weeks (p-value of .002), age and PCR at 24 weeks (p-value of .051) and between ALT levels and PCR at 4, 12 and 24 weeks follow up (p-value <0.005). At 1-year follow-up, 79.3% of cases achieved a negative PCR, 28 patients failed to be followed, 6.2% of cases had a positive PCR. 5.5% of cases of the total 163 SVR cases had a relapse at 1 year. CONCLUSIONS: HCV genotype 3 patients can benefit from Sofosbuvir and Ribavirin. With the SVR of more than 80%, this combination is cost-effective and safe. Treatment duration should be dependent on RVR and viral load at 4 weeks follow-up.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Estudos Transversais , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Recidiva , Estudos Retrospectivos
9.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652639

RESUMO

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.


Assuntos
Catequina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Proteínas do Envelope Viral/genética , Antivirais/química , Antivirais/farmacologia , Catequina/química , Catequina/farmacologia , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Polifenóis/química , Polifenóis/farmacologia , Chá/química , Envelope Viral/química , Proteínas do Envelope Viral/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacos
10.
Int J Infect Dis ; 105: 377-388, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33601031

RESUMO

OBJECTIVE: To characterize hepatitis C virus (HCV) infection epidemiology in Mongolia. METHOD: Publications on HCV antibody (Ab) and RNA prevalence, and/or genotypes/subtypes were systematically reviewed and reported following PRISMA guidelines. Random-effects meta-analyses and age adjustments were conducted to estimate the prevalence of Mongolians exposed to HCV (pooled HCV-Ab prevalence) by time period, sex, and at-risk populations; and to estimate the prevalence of chronically-infected HCV individuals. RESULTS: The national pooled HCV-Ab prevalence was 12.3% in 2000-2009 and 11.2% in 2013. Sex-specific pooled prevalence appeared higher among females than males (14.0% versus 6.8%). Age-specific pooled prevalence significantly increased from 3.7% among children (aged 0-10 years) to 34.1% among people aged ≥50 years (p < 0.001). Among the adult general population (low-risk population), the national age-adjusted prevalence was 8.1%. Age-adjusted chronic infection prevalence in adults was 6.0%. Among healthcare workers, pooled prevalence was 18.0%. Among patients with liver diseases, pooled prevalence was 53.7%. Among individuals engaging in risky sexual behaviors, pooled prevalence was 11.1%. The identified circulating genotypes/subtypes were 1b (58.0%), 2a (21.7%), and 1a (20.2%). CONCLUSION: The national HCV prevalence in Mongolia appeared to be among the highest worldwide. Higher prevalence in the clinical setting indicated potential ongoing HCV iatrogenic and occupational transmission. Additionally, HCV transmission in community settings should be investigated.


Assuntos
Hepacivirus/genética , Hepatite C/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Genótipo , Hepacivirus/classificação , Hepatite C/virologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mongólia/epidemiologia , Prevalência
11.
Mikrobiyol Bul ; 55(1): 30-40, 2021 Jan.
Artigo em Turco | MEDLINE | ID: mdl-33590979

RESUMO

Genotype distribution of hepatitis C virus (HCV) can vary over the years between different patient groups and regions. The prevalence of intravenous drug users (IVDU) is known to increase in our country, yet there are a limited number of studies investigating the distribution of HCV genotypes in this group. These data are essential for monitorization of the changes in HCV epidemiology. The present study aimed to evaluate the five-year results of HCV genotyping among patients infected with HCV related to IVDU and unrelated to drug use. Plasma samples of 720 patients (HCV antibody, HCV RNA positive), which were sent to our laboratory for HCV genotyping between January 2014-March 2019 were analyzed. HCV RNA extraction from plasma samples was performed in the automated-extraction system of EZ1 advanced (Qiagen, Germany) using the EZ1 virus mini kit v2.0 (Qiagen, Germany). Amplicons were obtained by amplifying the 5'NCR and core gene region in the Rotorgene 6000 real-time PCR (Qiagen, Germany) device with the HCV RNA real-time quantitative 2.0 (NLM, Italy) kit. For the genotyping, a commercial line probe assay (LIPA) based on in vitro reverse hybridization GEN-C2.0 kit (NLM, Italy) which can distinguish 1, 2, 3, 4, 6 genotypes and 1a, 1b, 2a/c, 2b, 3a, 3b, 3c, 3k, 4a, 4b, 4c/d, 4e, 4f, 4h, 5a, 6a/b, 6g, 6f/q, 6m, 7a subtypes of HCV, based on variations in the 5'-NCR and core regions was used. HCV genotype distribution of 266 IVDU (93.2%: male; median age: 25 ± 6.82) and 454 non-drug users (51.3%: male; median age: 56.5 ± 16.06) were examined. In order of frequency in the group with IVDU; genotype 1a, 3a, 1b, 4c/d, 2b, 4, 3 were observed and genotype 1, 2a/c and mixed genotype (1+3a) were detected in one patient. In the group without IVDU, in order of frequency; genotype 1b, 1a, 3a, 1, 2a/c, 4 were observed and genotype 2b, 4c/d, 5a, 6a/b, 6 and mixed genotype (3+4) were detected in one patient. Genotypes 1a and 3a were significantly higher in the IVDU group (p< 0.00001, p< 0.00001), while 1b was significantly higher in patients without IVDU (p< 0.00001). Genotypes 1a and 3a were more common in young men (p< 0.00001, p= 0.000163), while 1b was higher in middleaged women (p< 0.00001). The incidence of genotypes 1b (p= 0.021) and 3a (p= 0.012) was higher in foreign nationals than the Turkish patients. When the HCV genotype distribution was examined by years, it was observed that the percentages of genotype 1b and 1a were decreasing, while the percentage of genotype 3a was increasing. As a result, in this study, HCV genotype distribution among IVDU was observed to be different from the general population without IVDU. It was found that genotypes 1a and 3a were more common in the IVDU group. As in the other regions of our country, genotype 1b was found most frequently in the general population. Genotype 3a increases significantly compared to years. In our study, the determination of genotypes existing in different parts of the world may be due to the foreign nationals living in our city and our region is a tourism center. It is also necessary to investigate whether there is an increase in IVDU over the years.


Assuntos
Hepacivirus , Hepatite C , Adolescente , Adulto , Idoso , Usuários de Drogas/estatística & dados numéricos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Abuso de Substâncias por Via Intravenosa , Turquia/epidemiologia , Adulto Jovem
12.
BMC Infect Dis ; 21(1): 223, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637051

RESUMO

BACKGROUND: Despite a dramatic reduction in HCV drug costs and simplified models of care, many countries lack important information on prevalence and risk factors to structure effective HCV services. METHODS: A cross-sectional, multi-stage cluster survey of HCV seroprevalence in adults 18 years and above was conducted, with an oversampling of those 45 years and above. One hundred forty-seven clusters of 25 households were randomly selected in two sets (set 1=24 clusters ≥18; set 2=123 clusters, ≥45). A multi-variable analysis assessed risk factors for sero-positivity among participants ≥45. The study occurred in rural Moung Ruessei Health Operational District, Battambang Province, Western Cambodia. RESULTS: A total of 5098 individuals and 3616 households participated in the survey. The overall seroprevalence was 2.6% (CI95% 2.3-3.0) for those ≥18 years, 5.1% (CI95% 4.6-5.7) for adults ≥ 45 years, and 0.6% (CI95% 0.3-0.9) for adults 18-44. Viraemic prevalence was 1.9% (CI95% 1.6-2.1), 3.6% (CI95% 3.2-4.0), and 0.5% (CI95% 0.2-0.8), respectively. Men had higher prevalence than women: ≥18 years male seroprevalence was 3.0 (CI95% 2.5-3.5) versus 2.3 (CI95% 1.9-2.7) for women. Knowledge of HCV was poor: 64.7% of all respondents and 57.0% of seropositive participants reported never having heard of HCV. Risk factor characteristics for the population ≥45 years included: advancing age (p< 0.001), low education (higher than secondary school OR 0.7 [95% CI 0.6-0.8]), any dental or gum treatment (OR 1.6 [95% CI 1.3-1.8]), historical routine medical care (medical injection after 1990 OR 0.7 [95% CI 0.6-0.9]; surgery after 1990 OR 0.7 [95% CI0.5-0.9]), and historical blood donation or transfusion (blood donation after 1980 OR 0.4 [95% CI 0.2-0.8]); blood transfusion after 1990 OR 0.7 [95% CI 0.4-1.1]). CONCLUSIONS: This study provides the first large-scale general adult population prevalence data on HCV infection in Cambodia. The results confirm the link between high prevalence and age ≥45 years, lower socio-economic status and past routine medical interventions (particularly those received before 1990 and 1980). This survey suggests high HCV prevalence in certain populations in Cambodia and can be used to guide national and local HCV policy discussion.


Assuntos
Hepacivirus/imunologia , Hepatite C/epidemiologia , Viremia/epidemiologia , Adolescente , Adulto , Idoso , Camboja/epidemiologia , Estudos Transversais , Características da Família , Feminino , Hepacivirus/isolamento & purificação , Hepatite C/diagnóstico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Viremia/diagnóstico , Viremia/virologia , Adulto Jovem
13.
Viruses ; 13(2)2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33573191

RESUMO

Hepatocytes, the major target of hepatitis C virus (HCV), are highly polarized. HCV infection requires extensive trafficking to distinct subcellular domains in the polarized hepatocyte. Polarized cells and three-dimensional organoids are commonly used to study liver functions and differentiation. Researchers have begun adapting these cell culture models that morphologically and physiologically resemble hepatocytes in vivo to study HCV infection. This review summarizes the use of three-dimensional cell culture systems in studies of HCV infection.


Assuntos
Técnicas de Cultura de Células/métodos , Hepacivirus/fisiologia , Hepatite C/virologia , Animais , Técnicas de Cultura de Células/instrumentação , Hepacivirus/genética , Hepacivirus/crescimento & desenvolvimento , Hepatócitos/virologia , Humanos , Organoides/virologia
14.
Biomed Pharmacother ; 136: 111239, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33454599

RESUMO

Hepatitis C is an inflammatory liver disease caused by the single-stranded RNA (ssRNA) hepatitis C virus (HCV). The genetic diversity of the virus and quasispecies produced during replication have resulted in viral resistance to direct-acting antivirals (DAAs) as well as impediments in vaccine development. The recent adaptation of CRISPR-Cas as an alternative antiviral approach has demonstrated degradation of viral nucleic acids in eukaryotes. In particular, the CRISPR-effector Cas13 enzyme has been shown to target ssRNA viruses effectively. In this work, we have employed Cas13a to knockdown HCV in mammalian cells. Using a computational screen, we identified several potential Cas13a target sites within highly conserved regions of the HCV internal ribosomal entry site (IRES). Our results demonstrate significant inhibition of HCV replication as well as translation in huh-7.5 cells with minimal effects on cell viability. These findings were validated using a multi-modality approach involving qRT-PCR, luciferase assay, and MTT cell viability assay. In conclusion, the CRISPR-Cas13a system efficiently targets HCV in vitro, suggesting its potential as a programmable therapeutic antiviral strategy.


Assuntos
Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Marcação de Genes , Hepacivirus/genética , Hepatite C/terapia , Sítios Internos de Entrada Ribossomal , RNA Viral/genética , Proteínas Associadas a CRISPR/metabolismo , Linhagem Celular Tumoral , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/metabolismo , Hepatite C/genética , Hepatite C/virologia , Humanos , Estabilidade de RNA , RNA Viral/metabolismo , Replicação Viral/efeitos dos fármacos
15.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33431677

RESUMO

Hepatitis C virus (HCV) is a major worldwide health burden, and a preventive vaccine is needed for global control or eradication of this virus. A substantial hurdle to an effective HCV vaccine is the high variability of the virus, leading to immune escape. The E1E2 glycoprotein complex contains conserved epitopes and elicits neutralizing antibody responses, making it a primary target for HCV vaccine development. However, the E1E2 transmembrane domains that are critical for native assembly make it challenging to produce this complex in a homogenous soluble form that is reflective of its state on the viral envelope. To enable rational design of an E1E2 vaccine, as well as structural characterization efforts, we have designed a soluble, secreted form of E1E2 (sE1E2). As with soluble glycoprotein designs for other viruses, it incorporates a scaffold to enforce assembly in the absence of the transmembrane domains, along with a furin cleavage site to permit native-like heterodimerization. This sE1E2 was found to assemble into a form closer to its expected size than full-length E1E2. Preservation of native structural elements was confirmed by high-affinity binding to a panel of conformationally specific monoclonal antibodies, including two neutralizing antibodies specific to native E1E2 and to its primary receptor, CD81. Finally, sE1E2 was found to elicit robust neutralizing antibodies in vivo. This designed sE1E2 can both provide insights into the determinants of native E1E2 assembly and serve as a platform for production of E1E2 for future structural and vaccine studies, enabling rational optimization of an E1E2-based antigen.


Assuntos
Hepacivirus/efeitos dos fármacos , Anticorpos Anti-Hepatite C/biossíntese , Hepatite C/prevenção & controle , Proteínas do Envelope Viral/imunologia , Vacinas contra Hepatite Viral/imunologia , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/biossíntese , Mapeamento de Epitopos , Epitopos/química , Epitopos/imunologia , Feminino , Expressão Gênica , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Humanos , Imunogenicidade da Vacina , Camundongos , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Engenharia de Proteínas/métodos , Multimerização Proteica , Receptores Virais/genética , Receptores Virais/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Solubilidade , Tetraspanina 28/genética , Tetraspanina 28/imunologia , Vacinação , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Vacinas contra Hepatite Viral/administração & dosagem , Vacinas contra Hepatite Viral/química , Vacinas contra Hepatite Viral/genética
16.
Lancet Gastroenterol Hepatol ; 6(3): 169-184, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33515496

RESUMO

BACKGROUND: Treatment for infection with hepatitis C virus (HCV) during pregnancy has not yet been approved; however, interventions specifically targeting women, especially those of childbearing age (15-49 years), could prevent vertical transmission and community spread. To assess the impact of such interventions, improved prevalence estimates in this group are needed. We aimed to estimate the global prevalence of viraemic HCV in 2019 among women of childbearing age. METHODS: In this modelling study, we used previously developed models for 110 countries inputted with country-specific demographic and HCV epidemiology data. We did a literature review, searching PubMed, Embase, and grey literature for studies published between Jan 1, 2000, and June 30, 2018, reporting HCV antibody or viraemic prevalence in women of childbearing age. Studies from the literature review and studies in models were compared by use of a data quality scoring system and models were updated, as appropriate, when a better study was identified. We used these HCV disease burden models to calculate the 2019 prevalence of viraemic HCV in women of childbearing age. In countries without a model, prevalence was extrapolated by Global Burden of Disease (GBD) region. FINDINGS: An estimated 14 860 000 (95% uncertainty interval [UI] 9 667 000-18 282 000) women aged 15-49 years had HCV infection worldwide in 2019, corresponding to a viraemic prevalence of 0·78% (95% UI 0·62-0·86). Globally, HCV prevalence increased with age, rising from 0·25% (95% UI 0·20-0·27) in women aged 15-19 years to 1·21% (0·97-1·34) in women aged 45-49 years. China (16% of total infections) and Pakistan (15%) had the greatest numbers of viraemic infections, but viraemic prevalence was highest in Mongolia (5·14%, 95% CI 3·46-6·28) and Burundi (4·91%, 3·80-18·75). Of the countries with 500 cases or more, viraemic prevalence was lowest in Chile (0·07%, 95% UI 0·04-0·12). Among the GBD regions, eastern Europe had the highest viraemic prevalence (3·39%, 95% UI 1·88-3·54). By WHO region, the Eastern Mediterranean region had the highest viraemic prevalence (1·75%, 95% UI 1·26- 1·90). INTERPRETATION: Most research on HCV disease burden among women aged 15-49 years focuses on pregnant women. Using modelling, this analysis provides global and national estimates of HCV prevalence in all women of childbearing age. These data can inform preconception test-and-treat strategies to reduce vertical transmission and total disease burden. FUNDING: Gilead Sciences, John C Martin Foundation, private donors.


Assuntos
Hepatite C/tratamento farmacológico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Viremia/epidemiologia , Adolescente , Adulto , Feminino , Carga Global da Doença , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Pessoa de Meia-Idade , Modelos Teóricos , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , Prevalência , Literatura de Revisão como Assunto , Adulto Jovem
17.
Int J Mol Sci ; 22(3)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499186

RESUMO

Autophagy is a catabolic process that is important for maintaining cellular homeostasis. It is also known to possess other functions including protein trafficking and anti-microbial activities. Hepatitis C virus (HCV) is known to co-opt cellular autophagy pathway to promote its own replication. HCV regulates autophagy through multiple mechanisms to control intracellular protein and membrane trafficking to enhance its replication and suppress host innate immune response. In this review, we discuss the current knowledge on the interplay between HCV and autophagy and the crosstalk between HCV-induced autophagy and host innate immune responses.


Assuntos
Autofagia/fisiologia , Hepacivirus/fisiologia , Hepatite C/virologia , Transporte Proteico , Replicação Viral , Membrana Celular/metabolismo , Hepatite C/patologia , Hepatócitos/virologia , Homeostase , Humanos , Imunidade Inata , Microdomínios da Membrana , Mitocôndrias/metabolismo , Mitofagia , RNA Viral/metabolismo , Transdução de Sinais
18.
Arch Virol ; 166(2): 501-510, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33394169

RESUMO

With the introduction of direct-acting antiviral treatment (DAA), Tunisia has committed to achieving the international goal of eliminating viral hepatitis. Because the specific DAA prescribed depends on viral genotype, viral genotyping remains of great importance. The aim of the present study was to outline the trends in the distribution of HCV genotypes from 2002 to 2017 in the Tunisian general population in order to guide authorities towards the most appropriate therapeutic strategies for preventing HCV infection. A total of 2532 blood samples were collected over a 16-year period and from all regions of Tunisia. Genotyping showed that genotype 1 (subtype 1b) was the most prevalent genotype in the country (n = 2012; 79.5%), followed by genotype 2 (n = 339; 13.3%). Genotypes 3, 4 and 5 were detected in 4.8%, 2.2% and 0.1% of the country's population, respectively. Mixed infections with different HCV genotypes were detected in 0.1% of the population (one case each of genotypes 1b + 4, 1b + 2 and 2 + 4). Interestingly, a significant increase in genotypes 2, 3 and 4 was observed over time (p = 0.03). Sixteen different subtypes were detected over the study period, most of which were subtypes of genotype 2, and some of these subtypes appeared to be new. Patients infected with genotypes 1a, 3 and 4 were significantly younger than those infected with genotypes 1b and 2 (p < 0.01). Furthermore, genotypes 1b and 2 were detected more often in women than men, while genotypes 1a and 3 were detected mostly in men (P < 0.01). Our study confirms a large predominance of genotype1/subtype1b in Tunisia and shows a significant increase in the prevalence of other genotypes over time. These findings reinforce the need for an additional HCV genotype survey to improve the design of treatment strategies in Tunisia.


Assuntos
Hepacivirus/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Coinfecção/virologia , Feminino , Genótipo , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Tunísia , Adulto Jovem
19.
BMC Infect Dis ; 21(1): 102, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482747

RESUMO

BACKGROUND: In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms. METHODS: Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. RESULTS: The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38-5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45-5.43, 0.002 for rs12980275 and 2.44, 1.27-4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69-24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1. CONCLUSIONS: In haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.


Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/genética , Hepatite C/virologia , Interleucinas/genética , Diálise Renal/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Criança , Feminino , Genótipo , Hepatite C/epidemiologia , Humanos , Interferons/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Adulto Jovem
20.
Medicine (Baltimore) ; 100(2): e24137, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466187

RESUMO

ABSTRACT: To provide information and a basis for improved hepatitis C prevention and treatment, we aimed to determine the distribution of hepatitis C virus (HCV) genotypes among patients with hepatitis C from 4 ethnic minorities in Liaoning Province of China over the past 8 years and analyze and explore the virus' genotype evolution and possible clinical significance.For gene-sequencing, we collected peripheral blood samples of HCV-infected patients belonging to the Korean, Hui, Mongol, and Manchu ethnic minorities in Liaoning Province who were diagnosed at the Second Hospital of Dalian Medical University, Anshan Central Hospital, and the Second People's Hospital of Fuxin City between November 2011 and November 2019. To analyze genotype evolution and possible influencing factors, we determined the ratio of various genotypes. Among the 102 HCV-infected patients from 4 ethnic minorities in Liaoning Province, 46 had gene typing (GT)1b (45.10%), 15 had GT2a (14.71%), 14 had GT3a (13.73%), 13 had GT6a (12.75%), 3 had GT1a (2.94%), and 11 had an unclassified genotype (10.78%). The distribution of various genotypes in the Korean, Mongol, and Manchu ethnic minorities was significantly different (χ2 = 10.788, P = .029; χ2 = 7.846, P = .049; and χ2 = 22.400, P = .000, respectively). All ethnic minorities exhibited >40% of GT1b. In the Korean (14/33) and Manchu (14/30) ethnic minorities, the proportion of GT1b was significantly higher than those of other genotypes (P < .05). The ethnic Koreans had a high proportion of GT3a (18.18%, 6/33), whereas the ethnic Mongolians had a high proportion of GT6a (23.08%, 6/26). GT1a was only found in the Korean (6.06%, 2/33) and Manchu (3.33%, 1/30) ethnic minorities; in the Hui ethnic minority, only 3 genotypes were prevalent: GT1b, GT2, and GT3a. The ethnic minorities in Liaoning Province currently have diverse HCV genotypes; the most prevalent genotype is GT1b, followed by GT2a and GT3a, and the prevalence of GT3 and GT6 has increased. The distribution of HCV genotypes varies across different ethnic minorities. The Korean and Manchu ethnic minorities have the most prevalent genotypes, whereas the Hui ethnic minority has a relatively single distribution of the HCV genotype.


Assuntos
Grupos Étnicos/genética , Genótipo , Hepacivirus/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China/etnologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Hepatite C/etnologia , Hepatite C/genética , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade
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