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1.
N Engl J Med ; 384(6): 541-549, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33567193

RESUMO

BACKGROUND: A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS: In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS: A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS: In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).


Assuntos
Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/prevenção & controle , Imunogenicidade da Vacina , Vacinas contra Hepatite Viral/imunologia , Adenovirus dos Símios/genética , Adolescente , Adulto , Animais , Método Duplo-Cego , Feminino , Vetores Genéticos , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pan troglodytes , Abuso de Substâncias por Via Intravenosa , Linfócitos T/imunologia , Vacinas Sintéticas/imunologia , Vacinas contra Hepatite Viral/efeitos adversos , Adulto Jovem
2.
PLoS One ; 15(12): e0238540, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33347507

RESUMO

BACKGROUND: Autoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH. METHODS: We enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA. RESULTS: Serum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122-7471]) compared to those in CHC (1026 pg/ml [IQR: 806-1283] p<0.001), PBC (2395 pg/ml [IQR: 2012-3422] p<0.001) or healthy controls (1285 pg/ml [IQR: 1098-1812] p<0.001). In AIH group, serum sTIM-3 were correlated with alanine aminotransferase (ALT), or total bilirubin (TB) and negatively correlated with serum levels of albumin (Alb). Serum levels of sTIM-3 were also strongly correlated with Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum sTIM-3 levels (2147±623pg/ml versus 1321±378pg/ml, p<0.001). CONCLUSIONS: Circulating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted.


Assuntos
Galectina 3/metabolismo , Hepatite Autoimune/imunologia , Hepatite Autoimune/metabolismo , Domínios de Imunoglobulina/imunologia , Fígado/imunologia , Mucina-3/metabolismo , Linfócitos T/imunologia , Idoso , Alanina Transaminase/imunologia , Albuminas/metabolismo , Bilirrubina/metabolismo , Feminino , Glicosilação , Hepatite C Crônica/imunologia , Hepatite C Crônica/metabolismo , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo
3.
APMIS ; 128(11): 593-602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870528

RESUMO

Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant-immunomodulators (like oil bodies) offer cost-effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed-derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli- derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund's (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1-biased cellular responses, manifested by high levels of IFN-γ and lower IgG1/IgG2a ratio and IL-4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN-γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT-PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL-10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola-derived antigen and oil bodies in addressing these concerns.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Células Th1/efeitos dos fármacos , Proteínas do Core Viral/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo de Brassica napus/administração & dosagem , Óleo de Brassica napus/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/virologia , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/imunologia , Vacinas contra Hepatite Viral/biossíntese
4.
Mikrobiyol Bul ; 54(2): 279-290, 2020 Apr.
Artigo em Turco | MEDLINE | ID: mdl-32723283

RESUMO

Hepatitis C virus (HCV) infection is still an important public health problem worldwide. Cytokines play an important role in the prognosis of HCV infections. Polymorphisms in the cytokine genes can affect the gene expression and change the clinical course of the disease. The aim of this study was to determine the relationship between chronic hepatitis C and TNF-α rs1799964 (-1031 T/C), IL-12A rs568408 (3'UTR G/A), IL-12B rs3212227 (3'UTR A/C) and IFN-γ rs2430561 (+874 A/T) gene polymorphisms. A hundred patients with chronic hepatitis C and 100 healthy people as control group were included in the study. Approximately 2 ml peripheral blood was taken from the patient and control groups into tubes with EDTA and genomic DNA was obtained using the DNA isolation kit. Single nucleotide polymorphisms in TNF-α (rs1799964), IL-12A (rs568408), IL-12B (rs3212227) and IFN-γ (rs2430561) genes were investigated by using the real-time polymerase chain reaction (Rt-PCR) method. The data obtained were analyzed in SPSS package program. There was no statistically significant relationship between chronic hepatitis C and TNF-α and IFN-γ polymorphisms in terms of genotype and allele distributions (p> 0.05). However, it was found that the relationship between IL-12A (G/A) and IL-12B (A/C) polymorphisms was significant (p< 0.05). The frequencies of IL-12A GA (OR= 4.828, 95% CI= 1.452-16.046, p= 0.010) and AA genotypes (OR= 4.436, 95% CI= 1.398-14.077, p= 0.011) and A alele (OR= 1.602, 95% CI= 1.020-2.518, p= 0.040) were found to be higher in the patient group. When the relationship between chronic hepatitis C and IL-12B gene polymorphism was examined, it was determined that the frequencies of AC (OR= 2.060, 95% CI= 0.836-5.076, p= 0.116) and CC (OR= 3.020, 95% CI= 1.242-7.345, p= 0.015) genotypes and C allele (OR= 1.750, 95% CI= 1.152-2.659, p= 0.008) were high in the patient group. In addition, TNF-α TC/CC, IL-12A GA/AA, IL-12B AC/CC and IFN-γ TT genotypes were found to be 7.5 times higher in the patient group than the control group (OR= 7.500, 95% CI= 1.532-36.714, p= 0.013). Our results showed that IL-12A (3'UTR G/A) and IL-12B (3'UTR A/C) gene polymorphisms and TNF-α TC/CC, IL-12A GA/AA, IL-12B AC/CC and IFN-γ TT interactions may be effective in the risk of the chronicity of hepatitis C. However, further studies are needed to determine the role of polymorphisms in these cytokine genes in HCV infections.


Assuntos
Citocinas , Hepatite C Crônica , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Citocinas/genética , Citocinas/imunologia , Genótipo , Hepatite C Crônica/imunologia , Humanos
5.
J Virol ; 94(17)2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32554700

RESUMO

Hepatitis C virus (HCV) infection remains a major worldwide health problem despite development of highly effective direct-acting antivirals. HCV rapidly evolves upon acute infection and generates multiple viral variants (quasispecies), leading to immune evasion and persistent viral infection. Identification of epitopes of broadly neutralizing anti-HCV antibodies (nAbs) is critical to guide HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on trans-complementation of viral structural proteins. The HCV genome (JFH1 strain) lacking the structural protein-coding sequence can be efficiently rescued by ectopic expression of core-E1-E2-p7-NS2 (core-NS2) or core-E1-E2-p7 (core-p7) in trans, leading to production of single-round infectious virions designated HCVΔS. JFH1-based HCVΔS can be also rescued by expressing core-NS2 of other HCV genotypes, rendering it an efficient tool to display the structural proteins of HCV strains of interests. Furthermore, we successfully rescued HCVΔS with structural proteins from clinical isolates. Multiple viral structural proteins with different sensitivities to nAbs were identified from a same patient serum, demonstrating the genetic diversity of HCV quasispecies in vivo Interestingly, the structural protein-coding sequences of highly divergent viral quasispecies from the same patient can be clustered based on their hypervariable region 1 (HVR1) in viral envelope protein E2, which critically dictates the sensitivity to neutralizing antibodies. In summary, we developed a novel reverse genetics system that efficiently displays viral structural proteins from HCV clinical isolates, and analysis of quasispecies from the same patient using this system demonstrated that E2 HVR1 is the major determinant of viral evolution in vivo IMPORTANCE A cell culture model that can recapitulate the diversity of HCV quasispecies in patients is important for analysis of neutralizing epitopes and HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on trans-complementation of viral structural proteins (HCVΔS). This system can be used to display structural proteins of HCV strains of multiple genotypes as well as clinical isolates. By using this system, we showed that multiple different HCV structural proteins from a same patient were displayed on HCVΔS. Interestingly, these variant structural proteins within the same patient can be classified according to the sequence of HVR1in E2, which dictates viral sensitivity to nAbs and viral evolution in vivo Our work provided a new tool to study highly divergent HCV quasispecies and shed light on underlying mechanisms driving HCV evolution.


Assuntos
Hepacivirus/genética , Hepacivirus/metabolismo , Quase-Espécies/genética , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Proteínas Estruturais Virais/química , Proteínas Estruturais Virais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Epitopos/imunologia , Evolução Molecular , Genótipo , Células HEK293 , Hepatite C/virologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Evasão da Resposta Imune , Testes de Neutralização , Proteínas do Envelope Viral/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
6.
Isr Med Assoc J ; 22(2): 100-103, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32043327

RESUMO

BACKGROUND: Autoimmune hepatitis (AIH) may be associated with other autoimmune diseases. Autoantibodies are common in AIH suggesting their potential role in the pathogenesis of the disease. Among these autoantibodies, thyroid autoantibodies have been reported in patients with chronic hepatitis, with greater prevalence in patients with chronic hepatitis C infection. OBJECTIVES: To assess the prevalence of thyroid dysfunction among patients with AIH. METHODS: In this case-control, retrospective study, we examined patients diagnosed with AIH according to both the original and revised international AIH group scoring systems. Patients with other hepatic pathologies were excluded AIH was evaluated as an independent risk factor for thyroid disease by a logistic regression model. Univariate and multivariate regression analyses were conducted using hypothyroidism and hyperthyroidism as the dependent variables. RESULTS: Our cohort comprised 163 patients diagnosed with AIH and 1104 healthy age- and gender-matched controls. Hypothyroidism was more prevalent among those with AIH compared to controls (17.7% vs. 5%, respectively, 95% confidence interval [95%CI] 1.68-2.48, P < 0.001). Hyperthyroidism was more prevalent in AIH patients compared to controls (odds ratio 3.2% and 1.2%, respectively, 95%CI 1.68-2.47, P < 0.001). Using a multivariate logistic analysis, we found an independent association between AIH and hypothyroidism but not with hyperthyroidism. CONCLUSIONS: Thyroid dysfunction is more prevalent in patients with AIH. Whether thyroid dysfunction is the cause or a risk factor for AIH, or vice versa, is still unclear. Screening for thyroid dysfunction is warranted after AIH is diagnosed.


Assuntos
Hepatite Autoimune , Hipotireoidismo , Glândula Tireoide/imunologia , Adulto , Autoanticorpos/análise , Autoimunidade/imunologia , Estudos de Casos e Controles , Feminino , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/imunologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/epidemiologia , Hepatite Autoimune/imunologia , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Hipotireoidismo/imunologia , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Medição de Risco , Testes de Função Tireóidea/métodos , Testes de Função Tireóidea/estatística & dados numéricos
7.
Arch Virol ; 165(3): 583-592, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927635

RESUMO

Interferon lambda was discovered in recent years to be an antiviral agent, and research on different aspects of this antiviral factor in viral infection and investigations of its effectiveness are also progressing. The immunological effects of interferon lambda on different cell populations is not precisely known, which may be due to its use of a heterodimeric receptor consisting of IL-10R2 and IFN-λR1, which are not broadly expressed in all types of cells. In the present study, signaling by interferon lambda and its effect on the expression of hepatitis C virus (HCV) proteins were measured, and the expression pattern of some antiviral proteins and IL-10 levels were investigated in peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 50 patients with chronic genotype 1a HCV infection and 10 healthy individuals as controls. The PBMCs were treated with various doses of interferon lambda at different times of cultivation. Real-time PCR was used for relative quantification of Mxa, PKR, OAS, ISG15 and HCV core mRNAs. Expression of the NS5A protein was measured by flow cytometry, and IL-10 production was assessed by ELISA. A significant increase in the expression of mRNA encoding antiviral proteins and a decrease in the expression of mRNAs encoding the HCV core protein were observed when cells were treated with interferon lambda in an intermittent manner. The expression of HCV NS5A protein and interleukin 10 levels were also lower than in the control group. It was shown that the maximum antiviral effect of interferon lambda in PBMCs is dependent on the dose and treatment time.


Assuntos
Hepatite C Crônica/imunologia , Interferons/farmacologia , Interleucinas/farmacologia , Leucócitos Mononucleares/imunologia , Proteínas do Core Viral/biossíntese , Proteínas não Estruturais Virais/biossíntese , Adulto , Antivirais/farmacologia , Linhagem Celular , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/imunologia , Interferon-alfa/farmacologia , Interferons/imunologia , Interleucina-10/biossíntese , Interleucinas/imunologia , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , RNA Viral/biossíntese , Proteínas do Core Viral/genética
8.
J Clin Invest ; 130(2): 748-753, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31904583

RESUMO

Chronic hepatitis C virus (HCV) infection is characterized by persistent high-level viremia and defective cellular immunity, including a lack of functional HCV-specific CD4+ T cells. We previously described an exceptional period of viral control that occurs in some chronically infected women after childbirth. Here, we investigated whether reduced HCV replication after pregnancy is associated with recovery of CD4+ T cell immunity. Class II tetramer analysis revealed significantly greater frequencies of circulating HCV-specific CD4+ T cells at 3 months postpartum in women with concurrent declines in viremia compared with those with stable viremia. These HCV-specific CD4+ T cells had an effector-memory phenotype. Inhibitory coreceptor expression on these cells corresponded to the degree of viral control. Circulating CD4+ T cells produced IL-2 and IFN-γ after HCV antigen stimulation, demonstrating Th1 functionality. These data provide direct evidence that the profound loss of HCV-specific CD4+ T cell help that results in chronic infection is reversible following pregnancy, and this recovery of CD4+ T cells is associated with at least transient control of persistent viral replication.


Assuntos
Hepacivirus/fisiologia , Hepatite C Crônica/imunologia , Parto , Complicações Infecciosas na Gravidez/imunologia , Células Th1/imunologia , Replicação Viral/imunologia , Adulto , Feminino , Hepatite C Crônica/patologia , Humanos , Interferon gama/imunologia , Interleucina-2/imunologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Células Th1/patologia
9.
World J Gastroenterol ; 26(2): 109-133, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31969775

RESUMO

At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.


Assuntos
Hepatite C Crônica/patologia , Cirrose Hepática/imunologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Imunidade Adaptativa , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Reposicionamento de Medicamentos , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Imunidade Inata , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Inflamassomos/imunologia , Inflamassomos/metabolismo , Lipogênese/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Cirrose Hepática/terapia , Miofibroblastos/transplante , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Resultado do Tratamento
10.
Transplant Proc ; 52(1): 97-101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31901328

RESUMO

BACKGROUND: In patients with hepatitis C virus (HCV) infection, the activation of the immune system by the virus or viral proteins leads to the production of numerous autoantibodies and clinical manifestations. The objectives of this study were to investigate the relationship between HCV and anti-HLA antibodies, as well as the effect of viremia on the antibody response and of direct-acting antivirals (DAAs) on anti-HLA antibody persistence in patients on the waiting list for a cadaveric kidney transplant. METHODS: A total of 395 patients from the cadaveric renal transplant waiting list were included in the study. The patients were grouped according to the presence of HCV infection, and patients with HCV positivity were further divided into a spontaneous clearance group and a persistent group. Anti-HLA antibodies were examined before and after treatment of the patients in the persistent group. The One Lambda Luminex method (Thermo Fisher Scientific, Waltham, MA, United States) was used to assess both HLA class I and II alleles and the anti-HLA antibody profile. RESULTS: Anti-HLA class I and II antibodies were detected in 48.2% and 55.1%, respectively, of the patients infected with HCV and in 21.8% and 20.4%, respectively, of the patients who were not infected. The level of anti-HLA A3, A11, B72, B52, Cw6, Cw16, DR3, and DQ4 antibodies was significantly higher in the patients infected with HCV. There was no statistically significant difference in class I and II antibody titration between the HCV-infected spontaneous clearance group and the persistent group (class I mean fluorescence intensity [MFI] ± SD: 13,583 ± 6224, 13,450 ± 9540, P = .808; Class II MFI ± SD: 13,000 ± 8673, 8440 ± 8302, P = .317, respectively). There was no significant difference in the class I and class II anti-HLA antibody profile and titration in the persistent group after treatment with DAAs (P > .05). CONCLUSIONS: The results of this study demonstrated that hepatitis C DAA treatment did not change the anti-HLA antibody profile and titration.


Assuntos
Antivirais/uso terapêutico , Autoanticorpos/efeitos dos fármacos , Hepacivirus/imunologia , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim , Adulto , Antivirais/imunologia , Autoanticorpos/imunologia , Cadáver , Feminino , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Viremia/tratamento farmacológico , Viremia/imunologia , Viremia/virologia , Listas de Espera
11.
Clin Exp Med ; 20(1): 131-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31664538

RESUMO

Value of hepatitis C virus (HCV) core antigen (cAg) test has been controversy in patients with low HCV loads for its lower sensitivity. We assessed correlation between HCV-cAg and HCV RNA in serum samples with low viral loads and analyzed the performance of HCV-cAg assay in determining diagnosis and treatment outcomes in chronic hepatitis C patients. Both HCV RNA and HCV-cAg were detected for 2298 serum samples. Correlation analysis was performed between the two tests. Receiver operating characteristics (ROC) curve was used to assess value of HCV-cAg test in determining diagnosis and response outcomes at the different HCV RNA thresholds. The two tests were correlated very well, and moreover, correlation in the low viral load group was higher than that in the high viral load group (r value: 0.901 and 0.517). Positive agreement of HCV-cAg ≥ 3 fmol/L was as high as 97.0% for HCV RNA ≥ 1000 IU/mL, and its negative agreement for HCV RNA < 15 IU/mL was up to 98.9% in all samples. Area under ROCs ranged from 0.939 to 0.992, regardless of HCV RNA thresholds. When lower limit of detection of HCV RNA was 15, 100 or 1000 IU/mL, positive predictive value of HCV-cAg was 96.8%, 98.8% or 92.4%, and its negative predictive value was 87.0%, 89.9% or 98.3%, respectively, on the basis of different cutoff values. High-sensitivity HCV-cAg detection may likely replace HCV RNA to confirm the existence of HCV and to guide the treatment of chronic HCV infection.


Assuntos
Hepacivirus/genética , Hepatite C Crônica/diagnóstico , RNA Viral/genética , Proteínas do Core Viral/análise , Adulto , Ensaios Clínicos como Assunto , Feminino , Hepacivirus/imunologia , Antígenos da Hepatite C/análise , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Carga Viral
12.
Immunol Invest ; 49(4): 477-488, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31694423

RESUMO

Background: T regulatory cells (Tregs), through variable mechanisms, play a crucial role in Hepatitis C virus (HCV) chronicity and infection tolerance. A great speculation is posed regarding the level, role of Tregs in end-stage renal disease (ESRD), and the presence of associated factors that could influence the Tregs population. Accordingly, we aimed at studying the effect of HCV infection on peripheral CD4+CD25+Tregs population among patients on hemodialysis (HD) as well as the effect of other comorbidities on these cells.Patients and methods: A group of 77 patients on HD (32 were HD HCV+ and 45 were HD HCV-) and 80 healthy controls (HCs) were included in the study. Flow cytometric analysis was performed for identification and quantification of peripheral CD4+ CD25+Tregs.Results: The frequency of CD4+ CD25+Tregs increased significantly in HD patients compared to the HCs (p = <.0001 each). HCV posed no effect on peripheral CD4+ CD25+ Tregs in ESRD patients, when comparing HD HCV- and HD HCV+ groups. In the hypertensive HD HCV-, Tregs percentage was higher than that in the non-hypertensive. However, the difference was not statistically significant. No significant difference was detected between HD HCV- and HD HCV+ patients on the count and percentages of Tregs according to the duration of dialysis.Conclusion: Demonstrating that chronic HCV infection has no effect on CD4+ CD25+ Tregs cells levels in ESRD patients is of great importance to the success of future allografts in such patients.


Assuntos
Hepatite C Crônica/imunologia , Falência Renal Crônica/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Diabetes Mellitus/imunologia , Diabetes Mellitus/terapia , Feminino , Hepatite C Crônica/terapia , Humanos , Hipertensão/imunologia , Hipertensão/terapia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Renal
13.
J Clin Invest ; 130(2): 998-1009, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31697649

RESUMO

BACKGROUNDChronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODSHCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTSWe observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSIONWe identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDINGDeutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS.


Assuntos
Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Antivirais/administração & dosagem , Feminino , Citometria de Fluxo , Seguimentos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Th1/patologia
14.
Expert Rev Gastroenterol Hepatol ; 14(1): 27-37, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31868062

RESUMO

Introduction: Hepatitis C chronic infection has long been correlated with numerous systemic diseases, such as diabetes mellitus and hepatic steatosis. Recent studies have also revealed an association with atherosclerosis.Areas covered: An analysis is presented on the mechanisms through which the hepatitis C viral infection can lead to a systemic increase in pro-inflammatory markers, especially tumor necrosis factor-a and interleukin-6. The immunological imbalance created may, through different mechanisms, act on the metabolic pathways that contribute to the development of insulin resistance, the accumulation of lipids in the liver, and even the formation of atherosclerotic plaques. Moreover, an additional contributing factor to the above-mentioned metabolic derangements is the unopposed oxidative stress observed in chronic hepatitis C viral infection. The virus itself contributes to the formation of oxidative stress, through alterations in the trace metal homeostasis and its effect on pro-inflammatory cytokines, such as tumor necrosis factor-a.Expert opinion: The scope of this review is to emphasize the importance of the metabolic manifestations of hepatitis C viral infection and to elucidate the pathophysiological mechanisms behind their emergence.


Assuntos
Hepatite C Crônica/imunologia , Inflamação/imunologia , Doenças Metabólicas/imunologia , Estresse Oxidativo/imunologia , Biomarcadores/análise , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/fisiopatologia , Hepacivirus , Hepatite C Crônica/fisiopatologia , Humanos , Inflamação/fisiopatologia , Resistência à Insulina/imunologia , Interleucina-6/imunologia , Doenças Metabólicas/fisiopatologia , Fator de Necrose Tumoral alfa/imunologia
15.
Pan Afr Med J ; 37: 103, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425136

RESUMO

Introduction: active or chronic exacerbated forms of hepatitis C virus (HCV) infection subsequently progress to liver disease and human defensins has been determined to have some level of anti-viral properties invitro whilst the expression of T helper-1 cytokines is known to promote complete recovery from acute HCV infection. The study sought to determine relationship between these immune responses. Methods: a cross sectional descriptive study design was employed. Hundred and thirty-two individuals were assessed were assessed for to anti-HCV, HCV RNA, serum levels of human alpha defensins 1 (HAD-1) and human beta defensins 1 (HBD-1). T helper 1 cytokines (IL-2, IFN gamma, TNF alpha) secreted in serum were also analyzed using commercial ELISA assay. The study was conducted in Kumasi, Obuasi and Daboya in Ghana. Results: the serum mean concentrations of HAD-1, HBD-1, IL-2, IFN gamma and TNF alpha showed no significant difference in concentrations among participants with chronic, spontaneously recovered or negative to HCV infection (p>0.05). Persons with hepatitis B co-infection were more likely to develop chronic HCV infection (p=0.039). HAD-1 and HBD-1 showed significant positive association with IL-2 (p=0.000) whilst only HAD-1 positively correlated with IL-2 (p<0.000). Conclusion: the immunological markers determined had no association with the status of HCV infection. HAD-1 increased with increasing levels of IL-2. These findings suggest that during HCV infection, inflammatory response through the production of cytokines by IL-2 cells may affect the release of HAD-1 and HBD-1.


Assuntos
Citocinas/sangue , Hepatite C/virologia , alfa-Defensinas/sangue , beta-Defensinas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos Transversais , Feminino , Hepatite C/sangue , Hepatite C/imunologia , Hepatite C Crônica/sangue , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Adulto Jovem
16.
Viral Immunol ; 32(10): 453-462, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31755827

RESUMO

CD81 serves as an immune modulator, playing its role in tumor growth and metastasis of hepatitis C virus (HCV)-mediated hepatocellular carcinoma (HCC). CD81 serves as a coreceptor of viral entry and is found to be enriched in exosomes. HCV E2 protein when associated with CD81 may be responsible for B cell lymphoproliferative disorders, as extrahepatic manifestation. Studies predict that HCV association with exosomes, leads to the establishment of persistent infection, through immune evasion. Herein, we confirm the association of HCV particles with CD81+ exosomes. Breifly, exosomes were enriched from peripheral blood of chronic HCV patients who have developed HCC. Sideways, exosomes were also enriched from peripheral blood of healthy individuals, who exhibited normal liver function test profile and had no known infection. Isolation of subpopulation of CD81+ exosomes was performed through immunocapture, followed by detection using FACS. Scanning electron microscopy confirmed the physical association of a fraction of exosome with HCV. CD81+ exosomes from chronic HCV patients with HCC were more granulated and larger when compared with those enriched from a healthy individual and HCV RNA was also detected in enriched fractions of CD81+ exosomes from HCV-positive HCC patients only, through real-time quantitative polymerase chain reaction. We concluded that CD81+ exosomes carry HCV particles and the association plays a pivotal role in establishing persistent infection, through immune evasion, thus leading to HCC progression. Exosomal CD81 and its interacting proteins might, therefore, serve as a potential prognostic marker and therapeutic target in HCV progression mediated by active HCV infection.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Exossomos/imunologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Neoplasias Hepáticas/diagnóstico , Tetraspanina 28/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Progressão da Doença , Exossomos/metabolismo , Exossomos/virologia , Feminino , Voluntários Saudáveis , Hepacivirus/isolamento & purificação , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Paquistão , Prognóstico , Tetraspanina 28/metabolismo , Adulto Jovem
17.
Cytokine ; 124: 154456, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31631862

RESUMO

Chronic hepatitis C (CHC) is frequently related to liver fibrosis, and several studies have suggested that the immunological activity of HCV antigens contributes to hepatic damage. In the present study, among structural and non-structural HCV antigens, elevatedIL-1ß, IL-6, IL-17 levels were secreted by PBMC cultures obtained from CHC patients following stimulation with core antigen. Moreover, the percentage of core-specific IL-6+IL-17+(CD4+ and CD8+) T cells was significantly higher in patients with worsehepatic lesions, determined on the Metavir scale. When compared with healthy subjects, the percentage of circulating Treg cells was elevated in CHC patients, mainly among those with advanced liver fibrosis. Nevertheless, in this last group of patients, the proportion of CD39+ Treg subsets was very low. Finally, the percentage of senescent (CD57+ CD28-) and exhausted (PD-1+CD28+) core-specific T cells in CHC patients was also found to be a result of fibrotic hepatic status. In summary, imbalances between different core-specific T cell subsets are associated with liver fibrosis severity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepatite C Crônica/imunologia , Cirrose Hepática/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Apirase/metabolismo , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD57/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Feminino , Hepacivirus , Humanos , Interleucina-17/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Células Th17/imunologia , Células Th17/metabolismo
18.
Sci Rep ; 9(1): 13300, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527718

RESUMO

Hepatitis C virus (HCV) is one of very few viruses that are either naturally cleared, or alternatively persist to cause chronic disease. Viral diversity and escape, as well as host adaptive immune factors, are believed to control the outcome. To date, there is limited understanding of the critical, early host-pathogen interactions. The asymptomatic nature of early HCV infection generally prevents identification of the transmitted/founder (T/F) virus, and thus the study of host responses directed against the autologous T/F strain. In this study, 14 rare subjects identified from very early in infection (4-45 days) with varied disease outcomes (n = 7 clearers) were examined in regard to the timing, breadth, and magnitude of the neutralizing antibody (nAb) response, as well as evolution of the T/F strain. Clearance was associated with earlier onset and more potent nAb responses appearing at a mean of 71 days post-infection (DPI), but these responses were narrowly directed against the autologous T/F virus or closely related variants. In contrast, a delayed onset of nAbs (mean 425 DPI) was observed in chronic progressors that appear to have targeted longitudinal variants rather than the T/F strain. The nAb responses in the chronic progressors mapped to known CD81 binding epitopes, and were associated with rapid emergence of new viral variants with reduced CD81 binding. We propose that the prolonged period of viremia in the absence of nAbs in these subjects was associated with an increase in viral diversity, affording the virus greater options to escape nAb pressure once it emerged. These findings indicate that timing of the nAb response is essential for clearance. Further investigation of the specificities of the early nAbs and the factors regulating early induction of protective nAbs is needed.


Assuntos
Anticorpos Neutralizantes/imunologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite C Crônica/imunologia , Tetraspanina 28/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Formação de Anticorpos/imunologia , Epitopos/imunologia , Feminino , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/sangue , Interações Hospedeiro-Patógeno/imunologia , Humanos , Estudos Longitudinais , Masculino , Proteínas do Envelope Viral/imunologia , Viremia/imunologia , Adulto Jovem
19.
Transpl Infect Dis ; 21(6): e13165, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31487082

RESUMO

Direct-acting antivirals (DAAs) demonstrated high efficacy and safety even in the post-liver transplant (LT) setting and in HIV-infected patients, but data are very limited in the early post-LT period with the most recently available DAA. Two HIV/HCV-coinfected LT recipients (both grafts from HIV/HCV-negative donors) experienced early HCV recurrence with severe hepatitis and were treated with sofosbuvir/velpatasvir for 12 weeks. Unfortunately, both patients failed: one (genotype 4d) showed virological breakthrough at week 3 with resistance-associated substitutions (RASs) for both NS5A and NS5B, while the other (genotype 1a) experienced virological relapse without RAS. Both progressed to fibrosing cholestatic hepatitis and were successfully retreated with glecaprevir/pibrentasvir for 16 weeks achieving sustained virological response. The higher prevalence of RAS in experienced genotype 4 patients and the long time to viral suppression observed in subjects with fibrosing cholestatic hepatitis should be taken into account, considering longer treatment duration to increase the chances of achieving sustained virological response.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Carbamatos/farmacologia , Infecções por HIV/complicações , Hepacivirus/isolamento & purificação , Hepatite C Crônica/terapia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Transplante de Fígado/efeitos adversos , Pirrolidinas/farmacologia , Quinoxalinas/farmacologia , Sofosbuvir/farmacologia , Sulfonamidas/farmacologia , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/virologia , Combinação de Medicamentos , Farmacorresistência Viral/genética , Infecções por HIV/imunologia , Infecções por HIV/terapia , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C Crônica/complicações , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/cirurgia , Cirrose Hepática/virologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/genética , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , RNA Viral/genética , RNA Viral/isolamento & purificação , Recidiva , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Resposta Viral Sustentada , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Proteínas não Estruturais Virais/genética
20.
J Immunol Res ; 2019: 5878960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485460

RESUMO

Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and "chronic hepatitis C virus (HCV) infection" (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.


Assuntos
Quimiocina CXCL10/sangue , Hepatite C Crônica/imunologia , Doença Aguda , Antivirais/uso terapêutico , Quimiocina CXCL10/genética , Hepatite C/imunologia , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , Imunomodulação , Interferon-alfa/uso terapêutico , Interferon gama/uso terapêutico , Interferons/genética , Fígado/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptores CXCR3/imunologia , Ribavirina/uso terapêutico
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