RESUMO
This study aims to explore the influence of coinfection with HCV and HIV on hepatic fibrosis. A coculture system was set up to actively replicate both viruses, incorporating CD4 T lymphocytes (Jurkat), hepatic stellate cells (LX-2), and hepatocytes (Huh7.5). LX-2 cells' susceptibility to HIV infection was assessed through measurements of HIV receptor expression, exposure to cell-free virus, and cell-to-cell contact with HIV-infected Jurkat cells. The study evaluated profibrotic parameters, including programed cell death, ROS imbalance, cytokines (IL-6, TGF-ß, and TNF-α), and extracellular matrix components (collagen, α-SMA, and MMP-9). The impact of HCV infection on LX-2/HIV-Jurkat was examined using soluble factors released from HCV-infected hepatocytes. Despite LX-2 cells being nonsusceptible to direct HIV infection, bystander effects were observed, leading to increased oxidative stress and dysregulated profibrotic cytokine release. Coculture with HIV-infected Jurkat cells intensified hepatic fibrosis, redox imbalance, expression of profibrotic cytokines, and extracellular matrix production. Conversely, HCV-infected Huh7.5 cells exhibited elevated profibrotic gene transcriptions but without measurable effects on the LX-2/HIV-Jurkat coculture. This study highlights how HIV-infected lymphocytes worsen hepatic fibrosis during HCV/HIV coinfection. They increase oxidative stress, profibrotic cytokine levels, and extracellular matrix production in hepatic stellate cells through direct contact and soluble factors. These insights offer valuable potential therapies for coinfected individuals.
Assuntos
Efeito Espectador , Técnicas de Cocultura , Coinfecção , Citocinas , Infecções por HIV , Hepacivirus , Células Estreladas do Fígado , Hepatite C , Cirrose Hepática , Humanos , Células Estreladas do Fígado/metabolismo , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Infecções por HIV/imunologia , Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Hepatite C/complicações , Hepatite C/imunologia , Células Jurkat , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Cirrose Hepática/etiologia , Citocinas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/virologia , HIV/fisiologia , Estresse Oxidativo , Comunicação Celular , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Matriz Extracelular/metabolismoRESUMO
Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQß1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQß1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQß1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQß1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQß1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.
Assuntos
Cadeias beta de HLA-DQ/genética , Hepacivirus/patogenicidade , Hepatite C/genética , Interações Hospedeiro-Patógeno/genética , Polimorfismo de Nucleotídeo Único , Doença Aguda , Alelos , Substituição de Aminoácidos , População Negra , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Cadeias beta de HLA-DQ/imunologia , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/imunologia , Hepatite C/etnologia , Hepatite C/imunologia , Hepatite C/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucina/imunologia , Leucina/metabolismo , Masculino , Prolina/imunologia , Prolina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Remissão Espontânea , População BrancaRESUMO
Female sex workers (FSWs) represent a high vulnerability group for the acquisition of sexual and parenteral infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. The present study aimed to determine the prevalence of serological markers and risk factors associated with exposure to HBV and HCV among FSWs in the state of Pará, Brazil. A cross-sectional study using principles of the time location sampling (TLS) method was conducted in four cities (Belém, Bragança, Barcarena, and Augusto Corrêa) of the state of Pará, from 2005 to 2006. In total, 365 FSWs were interviewed using a standardized questionnaire. Blood samples were collected and tested for serological markers of exposure to HBV and HCV using an enzyme immunoassay. The overall prevalence of exposure to HBV and HCV was 36.7% and 7.7%, respectively. The prevalence of surface antigen of HBV was 3.0%. The prevalence of anti-HBc and anti-HBc+ anti-HBs antibodies were 6.3% and 27.4%. Very few (4.7%) FSWs had vaccine immunity against HBV (anti-HBs antibodies only). The prevalence of anti-HCV antibodies was 7.7%. Low monthly income, drug usage, and unprotected sex were some of the social characteristics associated with exposure to the viruses using different analysis. The seroprevalence of HBV and HCV infections among FSWs in four cities of the state of Pará is high when compared to the general population of Brazil, but similar to those found in FSWs in other nondeveloped countries. The prevalence of HBV was higher in Belém, while the prevalence of HCV was higher in the other three cities, highlighting the importance of establishing control and prevention programs to reduce the risk of acquiring these viruses in Pará.
Assuntos
Hepatite B/epidemiologia , Hepatite B/imunologia , Hepatite C/epidemiologia , Hepatite C/imunologia , Profissionais do Sexo/estatística & dados numéricos , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Cidades/epidemiologia , Estudos Transversais , Feminino , Hepacivirus/imunologia , Hepatite B/sangue , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite C/sangue , Anticorpos Anti-Hepatite C/sangue , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Estudos Soroepidemiológicos , Adulto JovemRESUMO
INTRODUCTION: Hepatitis C virus (HCV) infection is a major health problem associated with considerable risk of mortality in different regions of the world. The purpose of this study was to investigate the contribution of HCV infection on all-cause and liver-related mortality, in a large cohort of blood donors in Brazil. METHODS: This is a retrospective cohort study of blood donors from 1994 to 2013, at Fundação Pró-Sangue-Hemocentro de São Paulo (FPS). This cohort included 2,892 and 5,784 HCV antibody seropositive and seronegative donors, respectively. Records from the FPS database and the Mortality Information System (SIM: a national database in Brazil) were linked through a probabilistic record linkage (RL). Mortality outcomes were defined based on ICD-10 (10th International Statistical Classification of Diseases and Related Health Problems) codes listed as the cause of death on the death certificate. Hazard ratios (HRs) were estimated for outcomes using Cox multiple regression models. RESULTS: When all causes of death were considered, RL identified 209 deaths (7.2%) among seropositive blood donors and 190 (3.3%) among seronegative blood donors. Donors seropositive for HCV infection had a 2.5 times higher risk of death due to all causes (95% CI: 1.76-2.62; p<0.001). When only liver-related causes of death were considered, RL identified 73 deaths among seropositive blood donors and only 6 among seronegative blood donors. Donors seropositive for HCV infection had a 23.4 times higher risk of death due to liver related causes (95% CI: 10.2-53.9; p<0.001). Donors seropositive for HCV had a 29.5 (95%CI: 3.9-221.7), 2.8 (95% CI: 1.4-5.5) and a 1.9 (95% CI: 1.2-3.0) times higher risk of death due to hepatocellular carcinoma, infection or trauma, respectively, compared to seronegative donors. CONCLUSIONS: All-cause and liver-related mortality rate was increased among blood donors seropositive for HCV compared with the mortality rate among seronegative blood donors. Our data confirms HCV as a relevant cause of death in Brazil and also suggest that interventions directed at following patients even after access to specific drug treatment are urgent and necessary.
Assuntos
Doadores de Sangue/estatística & dados numéricos , Anticorpos Anti-Hepatite C/sangue , Hepatite C/imunologia , Hepatite C/mortalidade , Adolescente , Adulto , Brasil , Estudos de Coortes , Feminino , Hepatite C/sangue , Humanos , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemAssuntos
Hepatite C/epidemiologia , Prisioneiros/estatística & dados numéricos , Viremia/epidemiologia , Adulto , Estudos Transversais , Feminino , Georgia/epidemiologia , Anticorpos Anti-Hepatite/sangue , Hepatite C/imunologia , Humanos , Modelos Logísticos , Masculino , New Mexico/epidemiologia , Prevalência , Prisões/estatística & dados numéricos , Viremia/imunologiaRESUMO
INTRODUCTION: HIV worsens HCV-related liver disease by accelerating fibrosis progression; however, progression rates are extremely variable among HIV/HCV-coinfected individuals. NK cells are associated with modulation of liver fibrosis and are profoundly altered during HCV and HIV infections. CD4+ T-cells modulate NK cell function, and are also affected by HIV infection. Here, we aim to characterize the association of hepatic fibrosis with both the phenotype and function of peripheral NK cells and their regulation by CD4+ T-cells, in HIV/HCV-coinfected individuals. METHODS: Thirty-four HIV/HCV-coinfected individuals with minimal (n = 16) and advanced (n = 18) fibrosis (METAVIR F0/F1 and F4 scores respectively) and 20 healthy volunteers were enrolled. PBMC were obtained from peripheral blood samples and NK and CD4+ T-cells were isolated and analysed. NK cell phenotype (CD25, CD69, Nkp46, NKG2D, PD-1), degranulation (CD107a) and IFN-γ and TNF-α production, as well as CD4+ T-cell activation (CD69, CD25 and CD38) were measured by flow cytometry. CD4+ T-cell conditioned medium (CM) derived from F0/F1 or F4 individuals was assessed for IL-2 levels by ELISA. Modulation of NK cell functionality by these CMs was also analysed. RESULTS: When comparing to NK cells from individuals with minimal fibrosis, degranulation and cytokine secretion by NK cells from subjects with F4 scores was significantly impaired, while PD-1 expression was augmented. On the one hand, neither the expression of activation markers nor IL-2 secretion was distinctly induced in CD4+ T-cells from subjects with F0/F1 or F4 METAVIR scores. Finally, NK cell degranulation and cytokine secretion were not differentially modulated by CD4+ T-cell CM, whether CD4+ T-cells derived from subjects with minimal or advanced fibrosis. CONCLUSIONS: Low levels of NK and CD4+ T-cells in HIV/HCV-coinfected individuals with advanced liver fibrosis have been previously described. Here, we show that advanced liver fibrosis in coinfected individuals is associated to a defective function of NK cells and an increased expression of the exhaustion/senescence marker PD-1. This NK signature could not be attributed to changes in the ability of CD4+ T-cells to modulate NK cell function.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Coinfecção/imunologia , Infecções por HIV/imunologia , Hepatite C/imunologia , Células Matadoras Naturais/imunologia , Cirrose Hepática/imunologia , Adulto , Idoso , Coinfecção/complicações , Coinfecção/virologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/virologia , HIV-1/fisiologia , Hepacivirus/fisiologia , Hepatite C/complicações , Hepatite C/virologia , Humanos , Leucócitos Mononucleares/imunologia , Cirrose Hepática/complicações , Cirrose Hepática/virologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Viral hepatitis is caused by different etiological agents with distinct epidemiological, clinical, and laboratory characteristics accounting for significant worldwide morbidity and mortality. Since 1996, the Brazilian Department of Sexually Transmitted Infections (STIs), Acquired Immune Deficiency Syndrome (AIDS) and Viral Hepatitis (DIAHV) in collaboration with the Ministry of Defense has been conducting periodic serosurveys of conscripts enlisted for the Brazilian army to assess STI prevalence and obtain data on knowledge and risk factors pertaining to STIs. This article aims to present the hepatitis B (hepatitis B surface antigen - HBsAg) and C (anti-HCV) seroprevalence estimates and risk factors as per the 8th edition of the Conscript Survey performed in 2016.This cross-sectional study was conducted among conscripts across Brazil aged 17 to 22 years from August to December 2016. It included a self-reported questionnaire and blood testing for syphilis, human immunodeficiency virus (HIV), and hepatitis B and C.In total 38,247 conscripts were enrolled; after applying exclusion criteria, 37,282 conscripts were included. The estimated HBsAg and anti-HCV prevalence rates were 0.22% and 0.28%, respectively. Higher HBsAg and anti-HCV prevalence rates were observed in the North Region (0.49%) and in the Central-west Region (0.65%), respectively. Regarding hepatitis B vaccination, 23.5% (nâ=â8412) of the individuals reported being unvaccinated and 47.4% (nâ=â16,970) did not know if they had been vaccinated. Among the anti-HCV positive conscripts, 53% (nâ=â51, 0.56%, Pâ=â.049) reported that they had never had sexual intercourse. Regarding self-reported STI status, most of the positive anti-HCV (nâ=â100, 0.29%, Pâ<â.01) and positive HBsAg (nâ=â76, 0.22%, Pâ=â.205) conscripts reported not having a STI. From those who tested positive for HBsAg, 89% (nâ=â42, 0.28%, Pâ=â.005) reported not making consistent use of condoms with steady partners.Our data suggest a low prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among Brazilian young men, and relatively low rates of self-reported HBV immunization. History of STIs, higher number of partners, inconsistent use of condoms, and lack of awareness of routes of transmission were significantly associated with HBV and HCV infections. To achieve the World Health Organization's goal of viral hepatitis elimination, access to hepatitis information, testing, and surveillance need to be improved.
Assuntos
Hepatite B/epidemiologia , Hepatite C/epidemiologia , Adolescente , Fatores Etários , Brasil/epidemiologia , Preservativos/estatística & dados numéricos , Estudos Transversais , Escolaridade , Conhecimentos, Atitudes e Prática em Saúde , Hepatite B/imunologia , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B/sangue , Vacinas contra Hepatite B/administração & dosagem , Hepatite C/imunologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Militares/estatística & dados numéricos , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Infecções Sexualmente Transmissíveis/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Hepatitis C virus (HCV) infection is associated with chronic liver disease, resulting in cirrhosis and hepatocellular carcinoma. Approximately 20% of HCV infections are spontaneously resolved. Here, we assessed the hierarchical relevance of host factors contributing to viral clearance. METHODS: DNA samples from 40 resolved infections and 40 chronic HCV patients paired by age were analyzed. Bivariate analysis was performed to rank the importance of each contributing factor in spontaneous HCV clearance. RESULTS: Interestingly, 63.6% of patients with resolved infections exhibited the protective genotype CC for SNP rs12979860. Additionally, 59.3% of patients with resolved infections displayed the protective genotype TT/TT for SNP ss469415590. Moreover, a ranking of clearance factors was estimated. In order of importance, the IL28B CC genotype (OR 0.197, 95% CI 0.072-0.541) followed by the INFL4 TT/TT genotype (OR 0.237, 95% CI 0.083-0.679), and female gender (OR 0.394, 95% CI 0.159-0.977) were the main predictors for clearance of HCV infection. CONCLUSIONS: HCV clearance is multifactorial and the contributing factors display a hierarchical order. Identifying all elements playing role in HCV clearance is of the most importance for HCV-related disease management. Dissecting the relevance of each contributing factor will certainly improve our understanding of the pathogenesis of HCV infection.
Assuntos
Hepacivirus/isolamento & purificação , Hepatite C/virologia , Adulto , Anticorpos Antivirais/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C/genética , Hepatite C/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores SexuaisRESUMO
BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are a common cause of complications in liver disease and immunological impairment among human immunodeficiency virus (HIV)-infected patients. The aim of this study was to assess the seroprevalence of HBV and HCV and their correlation with CD4+ T-cells among HIV-infected patients in an HBV endemic area. METHODS: A cross-sectional observational and retrospective study was carried out in a reference center in Southern Brazil between January 2005 and December 2016. Socio-demographic data were collected by using a structured questionnaire. Serological tests and analysis of CD4+ T-cell count levels were performed using standard procedures. RESULTS: The seroprevalence of HIV-HBV, HIV-HCV, and HIV-HBV-HCV coinfections was 3.10%, 3.10%, and 0.16%, respectively. At baseline, anti-hepatitis B surface and anti-hepatitis B core antigens were detected in 46.27% and 16.74% of HIV-monoinfected patients and in 31.25% and 21.86% of the HIV-HCV coinfected patients, respectively. The median CD4+ T-cell count at baseline in the HIV-monoinfected group was higher than that in the HIV-coinfected groups, but without statistical significance. The median CD4+ T-cell count and the CD4/CD8 ratio were significantly higher in HIV-HBV and HIV-HCV groups after 24 months of combination antiretroviral therapy (cART) compared to the pre-cART values. When comparing patients with HIV-HBV and HIV-HCV on cART, CD4+ T-cell recovery was more rapid for HIV-HBV patients. CONCLUSION: Although the analyzed region was endemic for HBV, the prevalence of HIV-HBV and HIV-HCV coinfection was lower than the rate found in the general population of Brazil. HBV and HCV had no significant impact on CD4+ T-cell counts among HIV-infected patients at baseline.
Assuntos
Coinfecção/epidemiologia , Infecções por HIV/epidemiologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Adulto , Fármacos Anti-HIV/administração & dosagem , Brasil/epidemiologia , Contagem de Linfócito CD4 , Coinfecção/tratamento farmacológico , Coinfecção/imunologia , Estudos Transversais , Quimioterapia Combinada , Doenças Endêmicas , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Hepatite B/tratamento farmacológico , Hepatite B/imunologia , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estudos Soroepidemiológicos , Carga Viral , Adulto JovemRESUMO
Acute hepatitis C virus (HCV) infection is usually asymptomatic, therefore, early diagnosis is rare. It may remain undiagnosed in individuals who progress to chronic infection, often until serious liver damage has developed. To incorporate the diagnosis of this viral disease in a multiple-diagnostic assay, we first analyzed by immunoinformatics the HCV subtype 1a polyprotein (specifically Core, E2, NS3, NS5A proteins) to select antigenic peptides to be tested initially by the Pepscan technique. Next, we performed the immunodiagnosis of HCV infection, using the Multiple Antigen Blot Assay (MABA). In 22 patients' sera included in this study, a 20-mer linear peptide belonging to the N-terminus of the worldwide conserved Core protein showed 100% sensitivity and specificity; other sequences showed different levels of antibody recognition. The use of MABA in combination with synthetic peptides as a source of multiple, specific, and nonexpensive antigens for other infectious diseases could represent a rapid, integrated, and inexpensive diagnostic methodology.