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1.
Rev Soc Bras Med Trop ; 52: e20190202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596352

RESUMO

INTRODUCTION: The prevalence of hepatitis C virus (HCV) infection is affected by demographic, virological, clinical, and lifestyle-related factors and varies in different regions in Brazil or worldwide. The present study aimed to clarify the epidemiological patterns of HCV infection in the interior region of Brazil. METHODS: This study was conducted in the Southern Triangle Macro-region of the state of Minas Gerais, Brazil, according to the guidelines of the National Program for the Prevention and Control of Viral Hepatitis. The participants answered a structured questionnaire on social and epidemiological factors. Immunochromatographic rapid tests were used for the qualitative detection of antibodies against HCV in whole blood (Alere HCV® Code 02FK10) in adult subjects by a free-standing method. RESULTS: Of 24,085 tested individuals, 184 (0.76%) were anti-HCV positive. The majority of anti-HCV-positive individuals were born between 1951 and 1980 (n=146 [79.3%]), with 68 women and 116 men. Identified risk factors included syringe and/or needle sharing (p = 0.003), being in prison (p = 0.004), and having tattoos or piercings (p = 0.005) and were significantly associated with the decade of birth. CONCLUSIONS: The study shows the importance of testing populations at risk for HCV infection, including incarcerated individuals, those with tattoos or piercings, those who share or have shared syringes or needles, and those in high-risk birth cohorts (1950s, 1960s, and 1970s) in the Southern Triangle Macro-region.


Assuntos
Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Hepatite C/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Estudos Transversais , Monitoramento Epidemiológico , Feminino , Hepatite C/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Adulto Jovem
2.
BMC Public Health ; 19(1): 1038, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375104

RESUMO

BACKGROUND: Age cohort screening for hepatitis C virus (HCV) might be an effective strategy if the majority of undiagnosed cases are concentrated in a particular age group. The objective of this study was to determine HCV prevalence in different age cohorts of the general population in the Central European part of Russia and second, to assess feasibility of HCV antigen testing for community screening programs. METHODS: Sera from 2027 volunteers were tested for anti-HCV (Architect Anti-HCV, Abbott Laboratories). All anti-HCV reactive samples were confirmed in an immunoblot and tested for HCV Ag (ARCHITECT HCV Ag, Abbott Laboratories), HCV RNA and HCV viral load. RESULTS: Out of 31 individuals with anti-HCV reactive result, 22 (71%) were confirmed by immunoblot, six were false positives and three were indeterminate. Active infection was observed in 73% of anti-HCV confirmed positives. Five out of 16 individuals had low HCV-RNA levels (< 10,000 IU/mL) and one of those had a very low level (594 IU/mL). Agreement between HCV Ag and HCV RNA was 100%. Total anti-HCV and active HCV infection rates were 1.09% (22/2027) and 0.79% (16/2027), respectively. The peak rates were observed in people 60 years or older (anti-HCV: 2.84% [95% CI: 1.66-4.74%], 13/319; HCV RNA/HCV Ag: 2.23% [95% CI: 1.20-4.00%], 10/319). CONCLUSIONS: Overall HCV prevalence is low, except in people 60 years or older. The latter should be considered as a target group for HCV screening. The high agreement between HCV RNA and HCV Ag suggests the utility of HCV Ag testing to confirm active infection in screening programs.


Assuntos
Serviços de Saúde Comunitária , Hepatite C/epidemiologia , Programas de Rastreamento/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Hepacivirus/genética , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/sangue , Antígenos da Hepatite C/sangue , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , RNA Viral/sangue , Federação Russa/epidemiologia , Adulto Jovem
3.
J Immunoassay Immunochem ; 40(5): 528-539, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31378189

RESUMO

Introduction: Hepatitis C virus (HCV) infects about 0.5% to 2.3% of the world population with most of the cases occurring in developing countries. It is primarily transmitted through transfusion of blood and blood products. There exists dearth of information on burden and circulation of HCV and their attendant health challenges in Nigeria. This study was therefore designed to determine the seroprevalence rate and risk of HCV transmission among blood donors in Lagos State Nigeria. Methodology: Blood samples were collected between January 2002 and December 2006 from 3,002 consenting (Male = 2,922; Female = 80; Age range = 18-63; Median age = 32 years) donors in five selected public hospitals' blood donation centers between 2002 and 2006. Sera was tested for anti-HCV by ELISA technique. Demographic and other relevant information were obtained by a semi-structured questionnaire to assess risk factors for HCV transmission. Results: This study found an overall rate of 3.1% for anti-HCV among the blood donors sampled. Highest rate of 6.0% for HCV was found among participants age ranged ≥50 years and lowest in the age group 40-49 years. Prevalence of HCV was higher in female (6.3%) than in male (3.0%) and was 0.21 times less risky in female compared to their male counterparts (OR = 1.29, 95%CI 0.11-1.31). By location, MSCH had the highest HCV rate (3.9%) and lowest (2.1%) in GHOA. Sharing of sharps for tattoo/tribal markings had a statistical association (p = .0379) with HCV infection. However, no significant difference was found by gender (CI = 0.99-2.01; p = .1002), age (CI = 0.79-1.55; p = .1001) and location (p = .5326). Conclusion: The relatively high prevalence of HCV infection detected and the risk of transmission among blood donors in this study are of public health importance. Hence, the institution of appropriate measures to stem down the trend of HCV circulation among this population in Nigeria is therefore advocated.


Assuntos
Doadores de Sangue , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/sangue , Hepatite C/transmissão , Adulto , Feminino , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Fatores de Risco , Estudos Soroepidemiológicos , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-31307313

RESUMO

A 38-year-old female with tricuspid atresia and normally related great arteries, initially palliated with Björk modified Fontan, and ultimately converted to extracardiac conduit Fontan, with a history of ventricular tachycardia and hepatitis C virus (HCV) treated with sofosbuvir/ledipasvir, was referred to our center for consideration of combined heart and liver transplantation. The patient's blood group was O with panel reactive antibodies of 52%. She consented to consideration of HCV-positive donors. Fifteen days later, an HCV-positive donor was identified, and she underwent heart transplantation with pulmonary artery reconstruction performed jointly by adult and pediatric transplant surgeons. To our knowledge, this the first time an HCV-positive donor heart has been to transplant an adult with congenital heart disease.


Assuntos
Cardiopatias Congênitas/cirurgia , Transplante de Coração/métodos , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite C/virologia , Doadores de Tecidos , Adulto , Feminino , Anticorpos Anti-Hepatite C/sangue , Humanos , Transplantados , Carga Viral
5.
APMIS ; 127(9): 642-652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274210

RESUMO

Hepatitis C virus (HCV) infection always leads to chronic hepatitis via dysregulation of host immunity. Notch signaling also modulates the response of monocytes/macrophages. Thus, we aimed to investigate the regulatory role of Notch signaling to CD14+ monocytes. Forty patients with chronic hepatitis C and twenty normal controls (NC) were enrolled. CD14+ monocytes and CD4+ T cells were purified from peripheral bloods. Notch receptors' mRNA expression in CD14+ monocytes was semi-quantified by real-time PCR. Cytokine production by CD14+ monocytes in response to γ-secretase inhibitor (GSI) was investigated by ELISA. GSI-induced CD14+ monocytes activity to HCV clearance in Huh7.5 cells and to CD4+ T cell differentiation was also assessed in direct and indirect contact co-culture system. Notch1 mRNA relative level was approximately 10-fold elevated in CD14+ monocytes from chronic hepatitis C patients when compared with NC. GSI stimulation resulted in enhanced cytokines production by CD14+ monocytes from chronic hepatitis C patients. GSI-stimulated CD14+ monocytes from chronic hepatitis C patients induced suppression of HCV RNA replication in both direct and indirect contact co-culture system of CD14+ monocytes and HCVcc-infected Huh7.5 cells, and this process was accompanied by elevation of interferon-γ production but not increased target cell death. Moreover, GSI stimulation also enhanced CD14+ monocytes-induced Th1 and Th17 cells activation, and this process required direct cell-to-cell contact. Effective antiviral therapy down-regulated Notch1 mRNA expression and promoted cytokine production by CD14+ monocytes from chronic hepatitis C. Current data revealed an important immunoregulatory property of Notch signaling to CD14+ monocytes in chronic HCV infection.


Assuntos
Hepatite C Crônica/imunologia , Monócitos/imunologia , Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Adulto , Linfócitos T CD4-Positivos , Diferenciação Celular/imunologia , Técnicas de Cocultura , Regulação para Baixo/imunologia , Feminino , Hepacivirus/imunologia , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th17/imunologia , Adulto Jovem
6.
Arch Virol ; 164(9): 2243-2253, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31179516

RESUMO

This study aimed to assess the seroprevalence, viraemia and genotype distribution of hepatitis C virus (HCV) in a region in Central-West Tunisia. A door-to-door cross-sectional study was conducted on a randomly selected sample. A total of 3178 individuals aged 5 to 74 years and members of 935 families were investigated. Seroprevalence of HCV was assessed using ELISA tests. The viral load was determined by real-time RT-PCR, and HCV genotyping was conducted by amplification and sequencing in the NS5b genomic region. The global prevalence of HCV antibodies was 3.32% (95% confidence interval [CI]: 2.72-4.00). It was significantly higher in women: 4.47% vs. 2.16% in men, p = 0.001. Seroprevalence increased with age, and the highest rates were found in the 50- to 59-year-old age group (12.90%, 95% CI: 9.45-16.86), suggesting a cohort effect with very low contribution of intrafamilial transmission. Genotyping showed a predominance of subtype 1b (84.6%), with cocirculation of subtypes 2c (9.6%), 1a (1.9%), 1d (1.9%) and 2k (1.9%), similar to the previously reported genotype distribution in Tunisia and with no genetic clusters specific to the study region. These results indicate a higher endemicity of HCV infection when compared to the previously reported nationwide surveillance data. This study provides valuable data that can contribute to current strategies to eliminate hepatitis C.


Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/epidemiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C/sangue , Hepatite C/virologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Prevalência , Estudos Soroepidemiológicos , Tunísia/epidemiologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/imunologia , Adulto Jovem
7.
Braz J Infect Dis ; 23(3): 173-181, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31228459

RESUMO

BACKGROUND: The prison system in Paraná, Brazil, is experiencing serious problems related to the increasing number of prisoners. Control of hepatitis C virus (HCV) has become more intense because the incarcerated population is considered a high-risk group for contagious diseases due to the favorable conditions found in prisons for the spread of these morbidities. The objective of this study was to identify features associated with hepatitis C infection among male prisoners in correctional institutions of Paraná state, Brazil. METHODS: This was a case-control study (27 cases and 54 controls) of men incarcerated in 11 penitentiaries in Paraná, Brazil. Information was obtained through a questionnaire in a cross-sectional epidemiological survey on HCV infection during the period from May 2015 to December 2016. Eligible men were recruited after testing positive for anti-HCV antibodies. Cases and controls were selected based on serological results of enzyme-linked immunosorbent assays and were matched by age, location of the penitentiary, and time in prison. Logistic regression analysis was used to identify risk factors for HCV seropositivity. RESULTS: The main significant independent risk factor for the acquisition of HCV infection was the use of injectable drugs (OR = 4.00; 95%CI:1.41-11.35; p < 0.001). CONCLUSIONS: This study provides evidence that HCV infection is associated with drug use by this population. This information is pivotal for tailoring prevention programs and guiding specific socioeducational measures that aim to reduce or prevent HCV transmission within the prison setting.


Assuntos
Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/sangue , Hepatite C/epidemiologia , Prisioneiros/estatística & dados numéricos , Adulto , Brasil/epidemiologia , Métodos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Fatores Socioeconômicos
8.
Nature ; 571(7764): 265-269, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207605

RESUMO

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Animais , Proliferação de Células , Doença Crônica , Citocinas/imunologia , Citocinas/metabolismo , Epigênese Genética , Feminino , Regulação da Expressão Gênica/imunologia , Hepacivirus/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Memória Imunológica , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Fenótipo , Timócitos/citologia , Timócitos/imunologia , Transcrição Genética
9.
Mol Immunol ; 111: 152-161, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054409

RESUMO

Despite successful anti-viral (DAAs) treatment of Hepatitis C virus (HCV) infection, recent data indicated the need for an effective vaccine. Preexisting anti-vector immunity is an obstacle for application of live vectors for antigen delivery and development of effective T-cell based HCV vaccines. Herein, we report construction of recombinant Leishmania tarentolae, a lizard (non-human) parasite, expressing an HCV polytope DNA, PT-NT(gp96), encoding for several immunogenic HCV epitopes and evaluation of its immunogenicity in three different prime/boost immunization groups (G) of BALB/c mice. Homologous prime/boost immunization by L.tarentolae-PT-NT(gp96) either with or without CpG (G1 and G2 respectively) and heterologous immunization with a PT-NT(gp96) encoding-pCDNA plasmid followed by L.tarentolae-PT-NT (G3) was undertaken. Immune responses were measured three and nine weeks (W) post immunization. Splenocytes (cultured with antigen-stimulant) of mice in G1 showed the highest percentage of specific CTL-cytolytic activity compared to G2 and G3 at both short (W3:70.98% versus 41.29% and 13.12%) and long (W9: 50% versus 24.5% and 20%) term periods, accompanied with high levels of secreted IFN-γ. Comparison of IFN-γ, IL-4, IL-17 and TNF-α cytokines levels obtained from the supernatant of antigen-stimulated splenocytes as well as antibodies level (as IgG1/IgG2a ratio; obtained from sera of immunized mice) indicated higher Th1 oriented responses for G1, G2 groups and balanced Th1-Th17 for G3. Results indicated the potential of L.tarentolae (+CpG), as a non-pathogenic live vaccine vector, for delivery and enhancement of immune responses against HCV-polytope antigens.


Assuntos
Hepacivirus/imunologia , Hepatite C/imunologia , Leishmania/imunologia , Células Th1/imunologia , Vacinas de DNA/imunologia , Animais , Citocinas/imunologia , DNA/imunologia , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Células Th17/imunologia , Vacinação/métodos
10.
PLoS Pathog ; 15(5): e1007772, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31100098

RESUMO

Cumulative evidence supports a role for neutralizing antibodies contributing to spontaneous viral clearance during acute hepatitis C virus (HCV) infection. Information on the timing and specificity of the B cell response associated with clearance is crucial to inform vaccine design. From an individual who cleared three sequential HCV infections with genotypes 1b, 1a and 3a strains, respectively, we employed peripheral B cells to isolate and characterize neutralizing human monoclonal antibodies (HMAbs) to HCV after the genotype 1 infections. The majority of isolated antibodies, designated as HMAbs 212, target conformational epitopes on the envelope glycoprotein E2 and bound broadly to genotype 1-6 E1E2 proteins. Further, some of these antibodies showed neutralization potential against cultured genotype 1-6 viruses. Competition studies with defined broadly neutralizing HCV HMAbs to epitopes in distinct clusters, designated antigenic domains B, C, D and E, revealed that the selected HMAbs compete with B, C and D HMAbs, previously isolated from subjects with chronic HCV infections. Epitope mapping studies revealed domain B and C specificity of these HMAbs 212. Sequential serum samples from the studied subject inhibited the binding of HMAbs 212 to autologous E2 and blocked a representative domain D HMAb. The specificity of this antibody response appears similar to that observed during chronic infection, suggesting that the timing and affinity maturation of the antibody response are the critical determinants in successful and repeated viral clearance. While additional studies should be performed for individuals with clearance or persistence of HCV, our results define epitope determinants for antibody E2 targeting with important implications for the development of a B cell vaccine.


Assuntos
Anticorpos Neutralizantes/imunologia , Desenho de Drogas , Hepacivirus/imunologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite C/prevenção & controle , Proteínas do Envelope Viral/imunologia , Vacinas contra Hepatite Viral/imunologia , Adulto , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Mapeamento de Epitopos , Genótipo , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Masculino , Testes de Neutralização , Estudos Prospectivos , Homologia de Sequência , Adulto Jovem
11.
Arch Virol ; 164(8): 2083-2090, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31134354

RESUMO

Although a few studies have been done on transmissible blood-borne viral infections in high-risk groups, little attention has been given to assessing the infection status of the general population in Afghanistan. To investigate the epidemiological status in the general population, we tested the serological markers of hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus (HDV), human immunodeficiency virus 1 (HIV-1) and human T-cell leukemia virus (HTLV) infections. In total, 492 samples were selected randomly from Nangarhar, Herat, Mazar-e Sharif, Kandahar, and Kabul from subjects between 25 and 70 years old. The samples were tested for the presence of HBsAg, anti-HBs, anti-HBc, anti-HDV, anti-HCV, anti-HIV-1 and anti-HTLV I/II antibodies using chemiluminescent immunoassays on Abbott Architect automated platforms. In addition, 220 HBsAg-positive samples identified among 5897 samples from the general population of the same regions of Afghanistan were included in the study and tested for both HBsAg and anti-HDV to investigate HDV prevalence in the country. Viral loads of HBV, HCV and HDV were determined in all seropositive samples using Ampliprep/Cobas TaqMan HBV, HCV, Test Roche (CA, USA), and an in-house method, respectively. Out of 492 samples, 31 (6.3%), 136 (27.6%) and 149 (30.3%) were found to be positive for HBsAg, anti-HBs and anti-HBc, respectively. Anti-HDV positivity was detected in five (2.1%) out of 234 HBsAg-positive samples (including 14 of the randomly selected samples that were not among the 220 previously identified as HBsAg positive). Only eight out of 492 (1.6%) subjects were positive for anti-HCV antibodies. Seven out of 489 (1.4%) were positive for anti-HIV-1 antibodies, and three out of 466 cases (0.6%) were positive for anti-HTLV I/II antibodies. These results suggest that Afghanistan is an intermediate endemic region for HBV, HDV and HCV infection. The prevalence of HIV-1 seems to be significantly higher than the global prevalence and that of the eastern Mediterranean region. In addition, the HTLV I/II screening results suggest that these viruses should be monitored in Afghanistan to confirm the trend observed in the current study.


Assuntos
Viroses/epidemiologia , Adulto , Afeganistão/epidemiologia , DNA Viral/genética , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1/imunologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite/imunologia , Hepatite B/epidemiologia , Hepatite B/imunologia , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite C/epidemiologia , Hepatite C/imunologia , Anticorpos Anti-Hepatite C/imunologia , Hepatite D/epidemiologia , Hepatite D/imunologia , Vírus Delta da Hepatite/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral/métodos , Viroses/imunologia
12.
Nat Commun ; 10(1): 2073, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061402

RESUMO

Isolation of broadly neutralizing human monoclonal antibodies (HmAbs) targeting the E2 glycoprotein of Hepatitis C virus (HCV) has sparked hope for effective vaccine development. Nonetheless, escape mutations have been reported. Ideally, a potent vaccine should elicit HmAbs that target regions of E2 that are most difficult to escape. Here, aimed at addressing this challenge, we develop a predictive in-silico evolutionary model for E2 that identifies one such region, a specific antigenic domain, making it an attractive target for a robust antibody response. Specific broadly neutralizing HmAbs that appear difficult to escape from are also identified. By providing a framework for identifying vulnerable regions of E2 and for assessing the potency of specific antibodies, our results can aid the rational design of an effective prophylactic HCV vaccine.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Proteínas do Envelope Viral/imunologia , Simulação por Computador , Desenho de Drogas , Mapeamento de Epitopos/métodos , Epitopos/genética , Epitopos/imunologia , Evolução Molecular , Hepacivirus/genética , Hepatite C/prevenção & controle , Hepatite C/virologia , Humanos , Modelos Biológicos , Proteínas do Envelope Viral/genética , Vacinas contra Hepatite Viral/imunologia
13.
Cells ; 8(4)2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959825

RESUMO

Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/imunologia , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Imunidade , Doença Aguda , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/virologia , Humanos , Imunidade/efeitos dos fármacos , Resultado do Tratamento
14.
Cell Host Microbe ; 25(5): 730-745.e6, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31003939

RESUMO

Type I interferon (IFN-I) is critical for antiviral defense, and plasmacytoid dendritic cells (pDCs) are a predominant source of IFN-I during virus infection. pDC-mediated antiviral responses are stimulated upon physical contact with infected cells, during which immunostimulatory viral RNA is transferred to pDCs, leading to IFN production via the nucleic acid sensor TLR7. Using dengue, hepatitis C, and Zika viruses, we demonstrate that the contact site of pDCs with infected cells is a specialized platform we term the interferogenic synapse, which enables viral RNA transfer and antiviral responses. This synapse is formed via αLß2 integrin-ICAM-1 adhesion complexes and the recruitment of the actin network and endocytic machinery. TLR7 signaling in pDCs promotes interferogenic synapse establishment and provides feed-forward regulation, sustaining pDC contacts with infected cells. This interferogenic synapse may allow pDCs to scan infected cells and locally secrete IFN-I, thereby confining a potentially deleterious response.


Assuntos
Antivirais/metabolismo , Adesão Celular , Células Dendríticas/imunologia , Imunidade Inata , Fatores Imunológicos/metabolismo , Interferon Tipo I/metabolismo , Viroses/imunologia , Linhagem Celular , Técnicas de Cocultura , Vírus da Dengue/imunologia , Hepacivirus/imunologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Receptor 7 Toll-Like/metabolismo , Zika virus/imunologia
15.
Nat Commun ; 10(1): 1507, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944315

RESUMO

Exhaustion of cytotoxic effector natural killer (NK) and CD8+ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/OTg mice permissive for persistent HCV infection, that NK and CD8+ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8+ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8+ T cell functions to prevent persistent HCV infection.


Assuntos
Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Células Matadoras Naturais/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Hepatite C Crônica/virologia , Hepatócitos/virologia , Antígenos de Histocompatibilidade Classe I/imunologia , Interferon gama/imunologia , Ativação Linfocitária/fisiologia , Proteínas de Membrana/imunologia , Camundongos , Distribuição Aleatória
16.
N Engl J Med ; 380(17): 1606-1617, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30946553

RESUMO

BACKGROUND: Hearts and lungs from donors with hepatitis C viremia are typically not transplanted. The advent of direct-acting antiviral agents to treat hepatitis C virus (HCV) infection has raised the possibility of substantially increasing the donor organ pool by enabling the transplantation of hearts and lungs from HCV-infected donors into recipients who do not have HCV infection. METHODS: We conducted a trial involving transplantation of hearts and lungs from donors who had hepatitis C viremia, irrespective of HCV genotype, to adults without HCV infection. Sofosbuvir-velpatasvir, a pangenotypic direct-acting antiviral regimen, was preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation, to block viral replication. The primary outcome was a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation. RESULTS: A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders. CONCLUSIONS: In patients without HCV infection who received a heart or lung transplant from donors with hepatitis C viremia, treatment with an antiviral regimen for 4 weeks, initiated within a few hours after transplantation, prevented the establishment of HCV infection. (Funded by the Mendez National Institute of Transplantation Foundation and others; DONATE HCV ClinicalTrials.gov number, NCT03086044.).


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Transplante de Coração , Hepacivirus/isolamento & purificação , Hepatite C/transmissão , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Transplante de Pulmão , Sofosbuvir/uso terapêutico , Adulto , Fatores Etários , Idoso , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Hepacivirus/imunologia , Hepatite C/prevenção & controle , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , RNA Viral/sangue , Doadores de Tecidos
17.
Viral Immunol ; 32(3): 112-120, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30817236

RESUMO

The present report describes current concepts about the mechanism of liver cell injury caused by host immune response against hepatitis C virus (HCV) infection in human beings. This report is based on the observations from experimental studies and follow-up actions on human liver diseases. The results from different investigations suggest that liver injury depends on the presentation of viral antigen and the level of host immune response raised against HCV-related peptides. Both innate and adaptive immunity are triggered to counter the viral onset. During development of host immunity, the cell-mediated immune response involving CD4+ Th1 cells and CD8+ cytotoxic T-lymphocyte (CTL) cells were found to play a major role in causing liver damage. The hepatic Innate lymphoid cells (ILCs) subsets are involved in the immune regulation of different liver diseases: viral hepatitis, mechanical liver injury, and fibrosis. Humoral immunity and natural killer (NK) cell action also contributed in liver cell injury by antibody-dependent cellular cytotoxicity (ADCC). In fact, immunopathogenesis of HCV infection is a complex phenomenon where regulation of immune response at several steps decides the possibility of viral elimination or persistence. Regulation of immune response was noted starting from viral-host interaction to immune reaction cascade engaged in cell damage. The activation or suppression of interferon-stimulated genes, NK cell action, CTL inducement by regulatory T cells (Treg), B cell proliferation, and so on was demonstrated during HCV infection. Involvement of HLA in antigen presentation, as well as types of viral genotypes, also influenced host immune response against HCV peptides. The combined effect of all these effector mechanisms ultimately decides the progression of viral onset to acute or chronic infection. In conclusion, immunopathogenesis of liver injury after HCV infection may be ascribed mainly to host immune response. Second, it is cell-mediated immunity that plays a predominant role in liver cell damage.


Assuntos
Imunidade Adaptativa , Hepatite C/imunologia , Hepatite C/patologia , Imunidade Celular , Fígado/imunologia , Fígado/patologia , Citocinas/imunologia , Hepacivirus/imunologia , Hepatócitos/imunologia , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Linfócitos/virologia , Linfócitos T Citotóxicos/imunologia
18.
Cells ; 8(3)2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909456

RESUMO

Innate immune responses generate interferons, proinflammatory cytokines, complement activation, and natural killer (NK) cell response. Ultimately, this leads to the induction of a robust virus-specific adaptive immunity. Although the host innate immune system senses and responds to eliminate virus infection, hepatitis C virus (HCV) evades immune attack and establishes persistent infection within the liver. Spontaneous clearance of HCV infection is associated with a prompt induction of innate immunity generated in an infected host. In this review, we have highlighted the current knowledge of our understanding of host⁻HCV interactions, especially for endogenous interferon production, proinflammatory response, NK cell response, and complement activation, which may impair the generation of a strong adaptive immune response for establishment of chronicity. The information may provide novel strategies in augmenting therapeutic intervention against HCV.


Assuntos
Hepacivirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Humanos , Inflamação/patologia , Interferons/biossíntese , Células Matadoras Naturais/imunologia
19.
Nat Commun ; 10(1): 1113, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846697

RESUMO

Efforts to develop an effective vaccine against the hepatitis C virus (HCV; human hepacivirus) have been stymied by a lack of small animal models. Here, we describe an experimental rat model of chronic HCV-related hepacivirus infection and its response to T cell immunization. Immune-competent rats challenged with a rodent hepacivirus (RHV) develop chronic viremia characterized by expansion of non-functional CD8+ T cells. Single-dose vaccination with a recombinant adenovirus vector expressing hepacivirus non-structural proteins induces effective immunity in majority of rats. Resolution of infection coincides with a vigorous recall of intrahepatic cellular responses. Host selection of viral CD8 escape variants can subvert vaccine-conferred immunity. Transient depletion of CD8+ cells from vaccinated rats prolongs infection, while CD4+ cell depletion results in chronic viremia. These results provide direct evidence that co-operation between CD4+ and CD8+ T cells is important for hepacivirus immunity, and that subversion of responses can be prevented by prophylactic vaccination.


Assuntos
Hepatite C Crônica/imunologia , Hepatite C Crônica/prevenção & controle , Linfócitos T/imunologia , Vacinas contra Hepatite Viral/farmacologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Hepacivirus/imunologia , Humanos , Evasão da Resposta Imune , Imunidade Celular , Depleção Linfocítica , Masculino , Ratos , Ratos Endogâmicos Lew , Vacinas Sintéticas/farmacologia , Viremia/imunologia , Viremia/prevenção & controle
20.
BMC Infect Dis ; 19(1): 128, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732573

RESUMO

BACKGROUND: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9 to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. METHODS: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. RESULTS: Five hundred ninety-seven individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were 'new positives' and 44% were 'known positives'. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. Forty-six subjects were referred to specialised services and two subjects completed HCV treatment. CONCLUSIONS: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV.


Assuntos
Assistência à Saúde/métodos , Hepatite C/diagnóstico , Pessoas em Situação de Rua , Adulto , Europa (Continente) , Feminino , Hepacivirus/imunologia , Hepatite C/epidemiologia , Anticorpos Anti-Hepatite C/sangue , Antígenos da Hepatite C/sangue , Humanos , Irlanda/epidemiologia , Masculino , Programas de Rastreamento , Prevalência , Inquéritos e Questionários
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