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1.
J Immunol ; 208(3): 672-684, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35022275

RESUMO

Hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection accelerates liver fibrosis progression compared with HBV or HCV monoinfection. Octamer binding transcription factor 4 (OCT4) and Nanog are direct targets of the profibrogenic TGF-ß1 signaling cascade. We leveraged a coculture model to monitor the effects of HBV and HCV coinfection on fibrogenesis in both sodium taurocholate cotransporting polypeptide-transfected Huh7.5.1 hepatoma cells and LX2 hepatic stellate cells (HSCs). We used CRISPR-Cas9 to knock out OCT4 and Nanog to evaluate their effects on HBV-, HCV-, or TGF-ß1-induced liver fibrogenesis. HBV/HCV coinfection and HBx, HBV preS2, HCV Core, and HCV NS2/3 overexpression increased TGF-ß1 mRNA levels in sodium taurocholate cotransporting polypeptide-Huh7.5.1 cells compared with controls. HBV/HCV coinfection further enhanced profibrogenic gene expression relative to HBV or HCV monoinfection. Coculture of HBV and HCV monoinfected or HBV/HCV coinfected hepatocytes with LX2 cells significantly increased profibrotic gene expression and LX2 cell invasion and migration. OCT4 and Nanog guide RNA independently suppressed HBV-, HCV-, HBV/HCV-, and TGF-ß1-induced α-SMA, TIMP-1, and Col1A1 expression and reduced Huh7.5.1, LX2, primary hepatocyte, and primary human HSC migratory capacity. OCT4/Nanog protein expression also correlated positively with fibrosis stage in liver biopsies from patients with chronic HBV or HCV infection. In conclusion, HBV and HCV independently and cooperatively promote liver fibrogenesis through a TGF-ß1-induced OCT4/Nanog-dependent pathway.


Assuntos
Hepatite B/patologia , Hepatite C/patologia , Cirrose Hepática/patologia , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Actinas/biossíntese , Adulto , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Coinfecção/patologia , Feminino , Técnicas de Inativação de Genes , Hepacivirus/metabolismo , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/virologia , Vírus da Hepatite B/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Fígado/patologia , Cirrose Hepática/virologia , Masculino , Proteína Homeobox Nanog/genética , Fator 3 de Transcrição de Octâmero/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Inibidor Tecidual de Metaloproteinase-1/biossíntese
2.
Virchows Arch ; 480(2): 335-347, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34498114

RESUMO

Sustained virological response (SVR) to the treatment of recurrent HCV in liver transplant recipients has excellent clinical outcomes; however, little is known about the effects on allograft histology. The study aimed to assess the histology of the allograft liver. In this single-center, retrospective cohort study, patients with recurrent hepatitis C (HCV) in allograft liver who were cured with antiviral therapy between 2010 and 2016 were identified. Biopsies were reviewed by two liver pathologists blinded to the treatment and SVR status. Paired analysis was performed to compare pre- and post-treatment histological features. Of the 62 patients analyzed, 22 patients received PEGylated interferon/ribavirin (IFN) therapy, while 40 patients received direct-acting antiviral agents (DAA). The mean age was 57 years, 24% were female, and 79% were Caucasian. RNA in situ hybridization testing for HCV and HEV was negative in all the tested patients. Significant reduction in the inflammatory grade of post-treatment biopsy specimens was noted in all subjects (n = 57; p < 0.001) and in the IFN group (n = 21; p = 0.001) but not in the DAA group (p = 0.093). Of all subjects, 21% had worsening stage, 31% had improvement, and 48% had no change in stage. Of the treatment groups, 27% in the IFN and 17% in the DAA groups had worsening stage; however, the results were not statistically significant in all subjects or by treatment modality. Persistent inflammatory infiltrates and fibrosis was noted in allograft tissue of patients cured with DAA. Significant improvement in grade was noted in the IFN group, without a significant change in stage.


Assuntos
Hepatite C Crônica , Hepatite C , Transplante de Fígado , Antivirais/uso terapêutico , Feminino , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Hepatite C Crônica/tratamento farmacológico , Humanos , Transplante de Fígado/efeitos adversos , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
3.
Anticancer Drugs ; 33(1): e36-e42, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34407041

RESUMO

Splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disease involving B-cells and affecting elderly patients. SMZL plague peripheral blood and bone marrow, spleen. Lymph nodes are generally spared. SMZL is due to a protracted antigen stimulation of B lymphocytes and of microenvironment leading B-cell to polyclonal and then oligoclonal/monoclonal growth, promoting lymphoproliferation. Integration of the NOTCH2 and NFk-B signaling has been recently identified as the primary mechanism of neoplastic proliferation in SMZL. In total 20% of cases carry mutations in NOTCH2. Although SMZL has an indolent course, progression to diffuse large B-cell lymphoma occurs in about 10-15% of patients. Establishing the prognosis is a key step in disease management, depending on both individual risk and patients' health status. This review discusses tailored treatment of SMZL patients. Progression risk factors include nodal and extra-nodal involvement, peripheral lymphocytosis, anemia and thrombocytopenia. Patients with two or more score points have a median survival of <5 years. Watch and wait strategy is appropriate in low-risk and asymptomatic patients, whereas treatment of symptomatic patients ranges from splenectomy to rituximab monotherapy or associated with chemotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/patologia , Medicina de Precisão/métodos , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/patologia , Antineoplásicos/uso terapêutico , Progressão da Doença , Hepatite B/patologia , Hepatite C/epidemiologia , Hepatite C/patologia , Humanos , Linfoma de Zona Marginal Tipo Células B/epidemiologia , Linfoma de Zona Marginal Tipo Células B/cirurgia , Linfoma Difuso de Grandes Células B/fisiopatologia , NF-kappa B/metabolismo , Estadiamento de Neoplasias , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Medição de Risco , Fatores de Risco , Transdução de Sinais , Esplenectomia , Neoplasias Esplênicas/epidemiologia , Neoplasias Esplênicas/cirurgia , Microambiente Tumoral/fisiologia
4.
Liver Int ; 42(4): 842-852, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34719118

RESUMO

BACKGROUND AND AIMS: Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. METHODS: Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age-adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N-acetyl-aspartate, choline, creatine, myo-inositol and glutamine + glutamate in frontal- (fWM) and parietal white matter (pWM). One-way analysis of variance and Kruskal-Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. RESULTS: HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N-acetyl-aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. CONCLUSION: The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.


Assuntos
Hepatite C , Hepatite Autoimune , Cirrose Hepática Biliar , Encéfalo/diagnóstico por imagem , Hepacivirus , Hepatite C/patologia , Humanos
5.
Curr Issues Mol Biol ; 43(3): 2022-2035, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34889885

RESUMO

Hepatitis C virus (HCV)-induced liver disease contributes to chronic hepatitis. The immune factors identified in HCV include changes in the innate and adaptive immune system. The inflammatory mediators, known as "inflammasome", are a consequence of the metabolic products of cells and commensal or pathogenic bacteria and viruses. The only effective strategy to prevent disease progression is eradication of the viral infection. Immune cells play a pivotal role during liver inflammation, triggering fibrogenesis. The present paper discusses the potential role of markers in cell death and the inflammatory cascade leading to the severity of liver damage. We aim to present the clinical parameters and laboratory data in a cohort of 88 HCV-infected non-cirrhotic and 25 HCV cirrhotic patients, to determine the characteristic light microscopic (LM) and transmission electron microscopic (TEM) changes in their liver biopsies and to present the link between the severity of liver damage and the serum levels of cytokines and caspases. A matched HCV non-infected cohort was used for the comparison of serum inflammatory markers. We compared the inflammation in HCV individuals with a control group of 280 healthy individuals. We correlated the changes in inflammatory markers in different stages of the disease and the histology. We concluded that the serum levels of cytokine, chemokine, and cleaved caspase markers reveal the inflammatory status in HCV. Based upon the information provided by the changes in biomarkers the clinician can monitor the severity of HCV-induced liver damage. New oral well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Therefore, using the noninvasive biomarkers to monitor the evolution of the liver damage is an effective personalized medicine procedure to establish the severity of liver injury and its repair.


Assuntos
Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Fígado/metabolismo , Fígado/virologia , Apoptose , Biomarcadores , Estudos de Casos e Controles , Morte Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Hepatite C/patologia , Humanos , Mediadores da Inflamação/metabolismo , Fígado/patologia , Fígado/ultraestrutura
6.
Viruses ; 13(12)2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34960690

RESUMO

Many people worldwide suffer from hepatitis C virus (HCV) infection, which is frequently persistent. The lack of efficient vaccines against HCV and the unavailability of or limited compliance with existing antiviral therapies is problematic for health care systems worldwide. Improved small animal models would support further hepacivirus research, including development of vaccines and novel antivirals. The recent discovery of several mammalian hepaciviruses may facilitate such research. In this study, we demonstrated that bank voles (Clethrionomys glareolus) were susceptible to bank vole-associated Hepacivirus F and Hepacivirus J strains, based on the detection of hepaciviral RNA in 52 of 55 experimentally inoculated voles. In contrast, interferon α/ß receptor deficient C57/Bl6 mice were resistant to infection with both bank vole hepaciviruses (BvHVs). The highest viral genome loads in infected voles were detected in the liver, and viral RNA was visualized by in situ hybridization in hepatocytes, confirming a marked hepatotropism. Furthermore, liver lesions in infected voles resembled those of HCV infection in humans. In conclusion, infection with both BvHVs in their natural hosts shares striking similarities to HCV infection in humans and may represent promising small animal models for this important human disease.


Assuntos
Arvicolinae , Modelos Animais de Doenças , Hepacivirus/fisiologia , Hepatite C , Animais , Feminino , Hepacivirus/isolamento & purificação , Hepacivirus/patogenicidade , Hepatite C/patologia , Hepatite C/transmissão , Hepatite C/veterinária , Hepatite C/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Fígado/patologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Carga Viral/fisiologia , Tropismo Viral
7.
Acta Crystallogr D Struct Biol ; 77(Pt 11): 1365-1377, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34726165

RESUMO

Hepatitis C virus (HCV) is an enveloped RNA virus. One of the hallmarks of HCV infection is a rearrangement of the host cell membranes, known as the `membranous web'. Full-field cryo soft X-ray tomography (cryo-SXT) in the water-window energy range (284-543 eV) was performed on the MISTRAL beamline to investigate, in whole unstained cells, the morphology of the membranous rearrangements induced in HCV replicon-harbouring cells in conditions close to the living physiological state. All morphological alterations could be reverted by a combination of sofosbuvir/daclatasvir, which are clinically approved antivirals (direct-acting antivirals; DAAs) for HCV infection. Correlatively combining cryo-SXT and 2D synchrotron-based infrared microscopy provides critical information on the chemical nature of specific infection-related structures, which allows specific patterns of the infection process or the DAA-mediated healing process to be distinguished.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Linhagem Celular , Hepacivirus/fisiologia , Hepatite C/patologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Microscopia , Espectroscopia de Infravermelho com Transformada de Fourier , Tomografia por Raios X
8.
Can J Gastroenterol Hepatol ; 2021: 4961919, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589447

RESUMO

Methods: Liver stiffness measurements (LSM) have been serially assessed 1, 3, and 5 years after HCV clearance in 655 patients who have been treated with DAAs. Results: The mean age was 51.44 ± 10 years. 73% of patients were males. 48% were cirrhotics. In noncirrhotics, the mean LSM was significantly decreased from 8.29 ± 2.3 kPa to 4.03 ± 1.0 kPa (p < 0.0001) at the end of the follow-up. Likewise, LSM decreased in cirrhotics from 29.66 ± 14.25 kPa to 22.50 ± 11.16 kPa (p < 0.0001). The proportions of F1, F2, F3, and F4 patients at the baseline were 17.7%, 17.9%, 16.6%, and 47.8%, which became 56.5%, 4.1%, 4.9%, and 34.5%, respectively, with a substantial reversal of cirrhosis in 87 patients (27.7%) at the end of follow-up. Conclusions: There was an overall significant regression of liver stiffness in all patients after sustained HCV eradication. Liver stiffness reflecting mild fibrosis (F0-F2) usually improves shortly after treatment, while measurements reflecting advanced fibrosis (F3-F4) take a longer time to regress to lower fibrosis stages.


Assuntos
Técnicas de Imagem por Elasticidade , Hepatite C Crônica , Hepatite C , Adulto , Egito/epidemiologia , Hepacivirus , Hepatite C/patologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade
9.
Cells ; 10(9)2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34571900

RESUMO

Iron is crucial to the regulation of the host innate immune system and the outcome of many infections. Hepatitis C virus (HCV), one of the major viral human pathogens that depends on iron to complete its life cycle, is highly skilled in evading the immune system. This study presents the construction and validation of a physiologically relevant triple-cell co-culture model that was used to investigate the input of iron in HCV infection and the interplay between HCV, iron, and determinants of host innate immunity. We recorded the expression patterns of key proteins of iron homeostasis involved in iron import, export and storage and examined their relation to the iron regulatory hormone hepcidin in hepatocytes, enterocytes and macrophages in the presence and absence of HCV. We then assessed the transcriptional profiles of pro-inflammatory cytokines Interleukin-6 (IL-6) and interleukin-15 (IL-15) and anti-inflammatory interleukin-10 (IL-10) under normal or iron-depleted conditions and determined how these were affected by infection. Our data suggest the presence of a link between iron homeostasis and innate immunity unfolding among liver, intestine, and macrophages, which could participate in the deregulation of innate immune responses observed in early HCV infection. Coupled with iron-assisted enhanced viral propagation, such a mechanism may be important for the establishment of viral persistence and the ensuing chronic liver disease.


Assuntos
Enterócitos/patologia , Hepatite C/patologia , Hepatócitos/patologia , Homeostase , Imunidade Inata , Ferro/metabolismo , Macrófagos/patologia , Técnicas de Cocultura , Citocinas/metabolismo , Enterócitos/imunologia , Enterócitos/metabolismo , Enterócitos/virologia , Hepacivirus/imunologia , Hepacivirus/metabolismo , Hepatite C/imunologia , Hepatite C/metabolismo , Hepatite C/virologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia
10.
PLoS Pathog ; 17(9): e1009889, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34492079

RESUMO

Hepatitis C virus (HCV) infection induces the degradation and decreases the secretion of apolipoprotein B (ApoB). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Therefore, HCV infection-induced degradation of ApoB may contribute to hepatic steatosis and decreased lipoprotein secretion, but the mechanism of HCV infection-induced ApoB degradation has not been completely elucidated. In this study, we found that the ApoB level in HCV-infected cells was regulated by proteasome-associated degradation but not autophagic degradation. ApoB was degraded by the 20S proteasome in a ubiquitin-independent manner. HCV induced the oxidation of ApoB via oxidative stress, and oxidized ApoB was recognized by the PSMA5 and PSMA6 subunits of the 20S proteasome for degradation. Further study showed that ApoB was degraded at endoplasmic reticulum (ER)-associated lipid droplets (LDs) and that the retrotranslocation and degradation of ApoB required Derlin-1 but not gp78 or p97. Moreover, we found that knockdown of ApoB before infection increased the cellular lipid content and enhanced HCV assembly. Overexpression of ApoB-50 inhibited lipid accumulation and repressed viral assembly in HCV-infected cells. Our study reveals a novel mechanism of ApoB degradation and lipid accumulation during HCV infection and might suggest new therapeutic strategies for hepatic steatosis.


Assuntos
Apolipoproteínas B/metabolismo , Fígado Gorduroso/virologia , Hepacivirus/metabolismo , Hepatite C/patologia , Linhagem Celular , Fígado Gorduroso/metabolismo , Hepatite C/metabolismo , Humanos , Oxirredução , Estresse Oxidativo/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo
11.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452505

RESUMO

Viral infection is a global public health threat causing millions of deaths. A suitable small animal model is essential for viral pathogenesis and host response studies that could be used in antiviral and vaccine development. The tree shrew (Tupaia belangeri or Tupaia belangeri chinenesis), a squirrel-like non-primate small mammal in the Tupaiidae family, has been reported to be susceptible to important human viral pathogens, including hepatitis viruses (e.g., HBV, HCV), respiratory viruses (influenza viruses, SARS-CoV-2, human adenovirus B), arboviruses (Zika virus and dengue virus), and other viruses (e.g., herpes simplex virus, etc.). The pathogenesis of these viruses is not fully understood due to the lack of an economically feasible suitable small animal model mimicking natural infection of human diseases. The tree shrew model significantly contributes towards a better understanding of the infection and pathogenesis of these important human pathogens, highlighting its potential to be used as a viable viral infection model of human viruses. Therefore, in this review, we summarize updates regarding human viral infection in the tree shrew model, which highlights the potential of the tree shrew to be utilized for human viral infection and pathogenesis studies.


Assuntos
Modelos Animais de Doenças , Tupaia , Viroses , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/virologia , Animais , COVID-19/virologia , Dengue/imunologia , Dengue/patologia , Dengue/virologia , Infecções por HIV/virologia , Hepatite B/imunologia , Hepatite B/virologia , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/imunologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
12.
Ann Clin Lab Sci ; 51(4): 512-520, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452889

RESUMO

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in IL28B and IL10 regions are important in predicting the antiviral response in hepatitis C virus (HCV) patients. In this study, the association of IL28B and IL10 genetic polymorphisms and other clinical factors was assessed as a predictive marker for the sustained virological response (SVR) of HCV patients taking direct-acting antivirals (DAAs). METHODS: We processed 384 serum specimens of HCV serology positive cases for qualitative and quantitative polymerase chain reaction (PCR). Patients were followed up for 12 weeks after the start of antiviral therapy, and the viral load was monitored at each time point. IL28B and IL10 polymorphisms (rs8103142 and rs12980275, rs1800872 and rs3021094, respectively) were detected by real-time PCR, followed by melt curve analysis for genotyping. RESULTS: This study's findings indicate an independent association of SVR with high basal viral load (P=0.005) and an HCV genotype other than 3 (P=0.001). Patients with viral load log10 >6.5 IU/mL required more days to reach an undetectable viral RNA load. The results of the genetic analysis showed a significant association of rs8103142 genotype CC (P<0.01) and rs12980275 genotype AA (P=0.01) with non-SVR. Both SNPs showed an independent association in the multivariate analysis. CONCLUSION: High basal viral load, HCV genotype, and host polymorphisms of rs8103142 and rs12980275 have an independent association in predicting the therapeutic response of HCV patients. The preliminary identification of polymorphisms prior to treatment will help in predicting the outcome of therapy.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C/patologia , Interferons/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Seguimentos , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/genética , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Carga Viral , Adulto Jovem
13.
Int J Biol Macromol ; 188: 147-159, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34371038

RESUMO

Hepatitis C virus (HCV) nonstructural protein NS4B is necessary for HCV replication. Our previous research found that NS4B-associated cellular proteins PREB and Surfeit 4 are involved in HCV replication. However, the molecular mechanism of HCV replication is not fully understood. Here we identified cellular ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) protein as a novel NS4B-associated HCV host cofactor by screening with small interfering RNA. Knockdown of OCIAD2 reduced significantly the HCV replication in a dose-dependent and genotype-independent manner. Further research showed that OCIAD2 was recruited into the HCV RNA replication complex by the interaction with NS4B. Interestingly, HCV replication induced OCIAD2 expression. In turn, overexpression of wild OCIAD2 also promoted virus replication whereas that of OCIAD2 mutant lacking the ability to bind NS4B exerted no effect on HCV replication. We also examined whether OCIAD2 interacted with other proteins participating in the HCV RNA replication complex including viral proteins NS5A, NS5B, and cellular proteins PREB, Surfeit 4. The results showed that OCIAD2 interacted with PREB and NS5A, but not NS5B or Surfeit 4. Our findings provide new insights into the function of OCIAD2 and HCV replication mechanism.


Assuntos
Hepacivirus/genética , Hepatite C/genética , Proteínas de Neoplasias/genética , Replicação Viral/genética , Linhagem Celular , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/genética , Genótipo , Fatores de Troca do Nucleotídeo Guanina/genética , Hepacivirus/patogenicidade , Hepatite C/patologia , Hepatite C/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas de Membrana/genética , Provírus/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição/genética , Proteínas não Estruturais Virais/genética
14.
PLoS One ; 16(7): e0254028, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34197557

RESUMO

BACKGROUND/AIMS: Hepatitis C Virus (HCV) infection is diagnosed by the presence of antibody to HCV and/or HCV RNA. This study aimed to evaluate the accuracy of anti-HCV titer (S/CO ratio) in predicting HCV viremia in patients with or without hepatitis B virus (HBV) dual infection. METHODS: Anti-HCV seropositive patients who were treatment-naïve consecutively enrolled. Anti-HCV antibodies were detected using a commercially chemiluminescent microparticle immunoassay. HCV RNA was detected by real-time PCR method. RESULTS: A total of 1321 including1196 mono-infected and 125 HBV dually infected patients were analyzed. The best cut-off value of anti-HCV titer in predicting HCV viremia was 9.95 (AUROC 0.99, P<0.0001). Of the entire cohort, the anti-HCV cut-off value of 10 provided the best accuracy, 96.8%, with the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 96.3%, 98.9%, 99.7% and 87.3% respectively. The best cut-off value of anti-HCV titer in predicting HCV viremia was 9.95 (AUROC 0.99, P<0.0001) and 9.36 (AUROC 1.00, P<0.0001) in patients with HCV mono-infection and HBV dual-infection respectively. Among the HBV dually infected patients, the accuracy of anti-HCV titer in predicting HCV viremia reached up to 100% with the cut-off value of 9. All the patients were HCV-viremic if their anti-HCV titer was greater than 9 (PPV 100%). On the other hand, all the patients were HCV non-viremic if their anti-HCV titer was less than 9 (NPV 100%). CONCLUSIONS: Anti-HCV titer strongly predicted HCV viremia. This excellent performance could be generalized to either HCV mono-infected or HBV dually infected patients.


Assuntos
Vírus da Hepatite B/isolamento & purificação , Hepatite B/sangue , Anticorpos Anti-Hepatite C/sangue , Hepatite C/sangue , Idoso , Feminino , Hepacivirus/isolamento & purificação , Hepacivirus/patogenicidade , Hepatite B/genética , Hepatite B/patologia , Vírus da Hepatite B/patogenicidade , Hepatite C/patologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , RNA Viral , Testes Sorológicos
15.
Cells ; 10(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209751

RESUMO

The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very­low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR­B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid­lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.


Assuntos
Hepacivirus/patogenicidade , Hipolipemiantes/farmacologia , Receptores de Lipoproteínas/metabolismo , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Linhagem Celular , Células Cultivadas , Colesterol/metabolismo , Estudos de Coortes , Genótipo , Glicoproteínas/metabolismo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/patologia , Hepatite C/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Receptores de Lipoproteínas/deficiência , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Sci Rep ; 11(1): 14506, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267267

RESUMO

Direct-acting antivirals (DAA) have replaced interferon (IFN)-based therapies for hepatitis C virus. In this retrospective clinical study, we examined differences in histopathologic features in paired liver biopsies collected from the same patient before and after DAA and correlated these findings with clinical outcome. Biopsies (n = 19) were evaluated by quantitative imaging analysis to measure steatosis and fibrosis. Most patients had decreased steatosis in their post-treatment, follow-up biopsies. However, one patient had a striking increase in steatosis (from 0.86 to 6.32%) and later developed decompensated cirrhosis and hepatocellular carcinoma (HCC). This patient had a marked increase in fibrosis between biopsies, with a CPA of 6.74 to 32.02. Another patient, who already had bridging fibrosis at the time of her pre-treatment biopsy, developed cholangiocarcinoma after DAA. Even though the overall inflammatory activity in the post-treatment biopsies significantly decreased after treatment, 60% of patients had persistent portal lymphocytic inflammation. In summary, DAAs decreased steatosis and hepatic inflammation in most patients, although some may have persistence of lymphocytic portal inflammation. Patients known to have advanced fibrosis at treatment initiation and who have other risk factors for ongoing liver injury, such as steatosis, should be followed closely for the development of adverse outcomes, such as portal hypertension and primary liver cancers.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Adulto , Fosfatase Alcalina/sangue , Biópsia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/virologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
17.
Metabolism ; 121: 154802, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34090869

RESUMO

Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.


Assuntos
Diabetes Mellitus/virologia , Hepacivirus/fisiologia , Hepatite C/complicações , Animais , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Hepatite C/metabolismo , Hepatite C/patologia , Hepatite C Crônica/complicações , Hepatite C Crônica/metabolismo , Hepatite C Crônica/patologia , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Transdução de Sinais/fisiologia
18.
BMC Cancer ; 21(1): 715, 2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34144696

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in Africa. In Africa, the major causes of HCC include chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Knowledge of the changes in the incidence of viral hepatitis-associated HCC over time and the factors responsible for such changes is key in informing policies for the prevention of viral hepatitis-associated HCC in Africa. AIM: The study aimed to systematically summarize the changes in the prevalence of viral hepatitis among HCC patients and the overall effect of the prevalence of viral hepatitis on the incidence of HCC over the past four decades in Africa (1980-2019). METHODS: A literature search was conducted in MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Web of Science, and African wide web for articles published on viral hepatitis-associated HCC in Africa from 1980 to 2019. The abstracts of the articles were screened for eligibility and those meeting the inclusion criteria were retrieved and reviewed. RESULTS: A total of 272 studies were included in the analysis. Viral hepatitis-related HCC incidence changed by 1.17% (95% confidence interval (CI): 0.63-1.71, p < 0.001), 0.82% (95% CI: 0.45-1.18, p < 0.001), and 3.34% (95% CI: 2.44-4.25, p < 0.001) for every 1% change in the prevalence of HBV, HCV, and hepatitis D virus (HDV) respectively, per decade. The incidence of HBV-related HCC decreased by - 0.50% (95% CI: - 0.74 - - 0.25, p < 0.001) over the last 40 years, while HCV-related HCC increased. CONCLUSION: Overall, the incidence of viral hepatitis-associated HCC has not declined, mainly due to no decline in the prevalence of HCV, HDV, and the high number of chronic hepatitis B carriers on the African continent. There is an urgent need for the allocation of resources for the implementation of treatment and preventive programs for HBV, HCV, HDV, and HCC in Africa. This systematic review is registered with PROSPERO®, number CRD42020169723.


Assuntos
Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Hepatite B/complicações , Hepatite C/complicações , Hepatite D/complicações , Hepatite Viral Humana/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , África , Carcinoma Hepatocelular/fisiopatologia , Hepatite B/patologia , Hepatite C/patologia , Hepatite D/patologia , Hepatite Viral Humana/patologia , Humanos , Neoplasias Hepáticas/fisiopatologia
19.
Clin Hemorheol Microcirc ; 79(4): 541-555, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34120896

RESUMO

BACKGROUND: A rapid decline of liver stiffness (LS) was detected by non-invasive methods in patients with chronic hepatitis C (HCV) infection during treatment with direct-acting antivirals (DAA). OBJECTIVE: To investigate the influence of inflammation on LS. METHODS: We prospectively examined LS by sonographic shear-wave elastography in 217 patients during DAA therapy from treatment initiation (BL) to 12 weeks after end of therapy (SVR12). Demographic data, laboratory findings and serum levels of cytokines were determined. RESULTS: Values of LS decreased from 1.86 m/s to 1.68 m/s (p = 0.01) which was most pronounced in patients who had F4 fibrosis at BL (3.27 m/s to 2.37 m/s; p < 0.001). Initially elevated values of aminotransferases, ferritin, IgG (p < 0.001 each) and international normalized ratio (p < 0.003) declined, thrombocyte count (p = 0.007) increased. Correlations of these laboratory parameters with BL levels of LS measurement (LSM) were most apparent in patients with F1-F3 fibrosis. Tumor necrosis factor (TNF)-α (p = 0.031), interleukin (IL)-10 (p = 0.005) and interferon y inducible protein (IP)-10 (p < 0.001) decreased in parallel with LSM under DAA therapy and corelated with BL values. CONCLUSION: Decrease of systemic inflammatory parameters correlated with LSM under DAA therapy. We conclude that regression of LSM is attributable to the decline of inflammation rather than reflecting fibrosis.


Assuntos
Técnicas de Imagem por Elasticidade , Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/patologia , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia
20.
PLoS One ; 16(5): e0251392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33961672

RESUMO

Chronic kidney disease (CKD) is one of the most well-known extrahepatic manifestations caused by hepatitis C infection (HCV). CKD is typically discovered at a late stage. HCV-nephropathy may show different histopathologic patterns, as both glomerular and tubulointerstitial damage have been described. Identification of patients with early renal manifestations would be beneficial to provide treatment and avoid progression to CKD. The observational prospective single-center HCVKID study assessed the prevalence of early renal manifestations in patients with chronic HCV and compared these patients with HCV-negative healthy controls cross-sectionally. HCV-positive patients with and without renal manifestations were also compared to define biomarkers suitable for identifying early manifestations in standard clinical practice. Tubular proteinuria as judged by urine α 1-microglobulin was the most common early renal manifestation found in 11% in HCV-positive patients, followed by hematuria in 8%. Kidney filtration was statistically significantly lower among HCV-positive patients with renal manifestation according to any calculation method. There were no significant differences in duration of infection or stage of liver fibrosis between patients with or without renal manifestations. Tubular cell damage may be the earliest sign of renal dysfunction caused by HCV. Complement activation also correlates with the dysfunction, indicating of contribution to HCV-induced renal manifestations even in their early phase.


Assuntos
Hepatite C/complicações , Túbulos Renais/patologia , Proteinúria/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Feminino , Hepatite C/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteinúria/etiologia , Proteinúria/patologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Adulto Jovem
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