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1.
Sci Rep ; 13(1): 22829, 2023 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-38129531

RESUMO

Hepatitis B virus (HBV)-transgenic mice exhibit competent innate immunity and are therefore an ideal model for considering intrinsic or cell-based mechanisms in HBV pathophysiology. A highly replicative model that has been little used, let alone characterized, is the Tg1.4HBV-s-rec strain derived from cross breeding of HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1-HBV]Bri44) or lack (Tg1.4HBV-s-mut) the hepatitis B surface antigen (HBsAg). Tg1.4HBV-s-rec hepatocytes secreted HBsAg, Hepatitis B extracellular antigen (HBeAg) and produced HBV virions. Transmission electron microscopy visualised viral particles (Tg1.4HBV-s-rec), nuclear capsid formations (Tg1.4HBV-s-mut and Tg1.4HBV-s-rec) and endoplasmic reticulum malformations (Alb/HBs). Viral replication in Tg1.4HBV-s-rec and Tg1.4HBV-s-mut differed in HBsAg expression and interestingly in the distribution of HBV core antigen (HBcAg) and HBV × protein. While in Tg1.4HBV-s-mut hepatocytes, the HBcAg was located in the cytoplasm, in Tg1.4HBV-s-rec hepatocytes, the HBcAg appeared in the nuclei, suggesting a more productive replication. Finally, Tg1.4HBV-s-rec mice showed symptoms of mild hepatitis, with reduced liver function and elevated serum transaminases, which appeared to be related to natural killer T cell activation. In conclusion, the study of Alb/HBs, Tg1.4HBV-s-mut and their F1 progeny provides a powerful tool to elucidate HBV pathophysiology, especially in the early HBeAg-positive phases of chronic infection and chronic hepatitis.


Assuntos
Hepatite A , Hepatite B , Camundongos , Animais , Vírus da Hepatite B/fisiologia , Antígenos de Superfície da Hepatite B/genética , Antígenos do Núcleo do Vírus da Hepatite B , Antígenos E da Hepatite B/genética , Antígenos da Hepatite B , Replicação Viral , Camundongos Transgênicos , DNA Viral , Fígado
2.
Carbohydr Polym ; 310: 120696, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-36925237

RESUMO

Highly branched α-glucan (HBAG) proved to be a promising material as an osmotic agent in peritoneal dialysis solutions. However, high resistance of HBAG to amylolytic enzymes might be a potential drawback for peritoneal dialysis due to its high degree of branching (20-30 %). To address this issue, we designed a small-clustered α-glucan (SCAG) with a relatively low molecular weight (Mw) and limited branching. Structural characteristics revealed that SCAG was successfully synthesized by modifying waxy rice starch (WRS) using sequential maltogenic α-amylase (MA) and starch branching enzyme (BE). The Mw of SCAG was 1.40 × 105 Da, and its (α1 â†’ 6) bonds ratio was 8.93 %, which was below that of HBAG. A relatively short branch distribution was observed in SCAG (CL = 6.27). Short-range orderliness of WRS was reduced from 0.749 to 0.322 with the MABE incubation. Additionally, SCAG had an extremely low viscosity (~12 cP) and nearly no retrogradation. Although the resistance of SCAG to amylolytic enzymes was enhanced by 15.22 % compared with native WRS, the extent was significantly lower than that of HBAG in previous studies. These new findings demonstrate the potential of SCAG as a novel functional α-glucan in food and pharmaceutical applications.


Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana , Oryza , Glucanos , Amilopectina/química , Enzima Ramificadora de 1,4-alfa-Glucana/química , Oryza/química , Antígenos da Hepatite B , Amido/química
3.
Technol Cancer Res Treat ; 21: 15330338221132669, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36254567

RESUMO

Background: Luminal B-like human epidermal growth factor receptor 2 negative (Luminal B [HER2-]) is the most common molecular subtype of breast cancer (BC). Since the relationship between Luminal B (HER2-) BC and liver metastasis (LM) is poorly defined, this retrospective study aimed to develop an LM risk nomogram for patients with lymph node-related (N + Luminal B [HER2-]) BC. Methods: Data were obtained for patients initially diagnosed with BC from the Tianjin Medical University Cancer Institute and Hospital. There were 30,975 Chinese female patients with stage I-III BC and follow-up confirming 1217 subsequent patients with LM, and 427 patients with N + Luminal B (HER2-). The LM risk was assessed using Cox proportional hazards regression, histogram, Venn diagram, and Kaplan-Meier survival analysis, with further analysis for patients with N + Luminal B (HER2-) BC. A nomogram was established based on the N + Luminal B (HER2-) BC data, which was validated using calibration plots. Results: The median age of 427 patients with N + Luminal B (HER2-) liver metastasis of breast cancer (BCLM) was 49 years. The largest number of patients with BCLM was diagnosed between the second to the 6th year, the longest interval from initial BC diagnosis to subsequent LM was 145 months. The patients with LM as the first site of distant metastasis which is associated with better survival were analyzed by Kaplan-Meier. The nomogram was constructed for the risk of LM that included age, menstrual status, unilateral oophorectomy, pregnancy, hepatitis B antigen, region of residence, tumor size, lymph node, clavicular lymph nodes, progesterone receptor, and lymph vessel invasion. Conclusion: We described the clinicopathological characteristics of patients with stage I-III BC, and constructed a nomogram for calculating personalized LM probabilities for patients with N + Luminal B (HER2-), which could guide future prolonged or early extensive treatment decisions.


Assuntos
Neoplasias da Mama , Neoplasias Hepáticas , Feminino , Humanos , Pessoa de Meia-Idade , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Antígenos da Hepatite B , Neoplasias Hepáticas/secundário , Metástase Linfática , Nomogramas , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Progesterona , Estudos Retrospectivos
4.
Talanta ; 249: 123659, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35728452

RESUMO

Quartz crystal microbalance (QCM)-based biosensors are highly attractive as rapid diagnostic devices for detecting infectious diseases. However, the fabrication of QCM-based biosensors often involves tedious processes due to the poor stability of the biological recognition elements. In this work, the simple self-polymerisation of dopamine was used to functionalise the QCM crystal surface with a molecularly imprinted polydopamine (MIPDA) sensing film for detecting the hepatitis B core antigen (HBcAg), a serological biomarker of hepatitis B. Recognition cavities that complemented the size and shape of HBcAg were observed on the QCM crystal surface after functionalisation with the MIPDA film. The MIPDA-QCM biosensor showed a selective affinity for HBcAg, recording frequency responses up to 7.8 folds larger towards HBcAg compared to human serum albumin at the same analyte concentrations. The biosensor response was enhanced by using the optimal concentrations of 10 mg mL-1 of dopamine and 1 mg mL-1 of template for MIPDA film formation, resulting in a low detection limit (0.88 µg mL-1) that enables the detection of clinically relevant titres of HBcAg. The detection process could be completed within 10 min after sample loading without additional steps for signal amplification, highlighting the practical advantages of the MIPDA-QCM biosensor for point-of-care detection of hepatitis B.


Assuntos
Técnicas Biossensoriais , Hepatite B , Impressão Molecular , Técnicas Biossensoriais/métodos , Dopamina , Hepatite B/diagnóstico , Antígenos da Hepatite B , Antígenos do Núcleo do Vírus da Hepatite B , Humanos , Indóis , Impressão Molecular/métodos , Polímeros , Quartzo , Técnicas de Microbalança de Cristal de Quartzo
5.
J Virol ; 96(2): e0136021, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34705558

RESUMO

Hepatitis B virus (HBV) utilizes host DNA repair mechanisms to convert viral relaxed circular DNA (rcDNA) into a persistent viral genome, the covalently closed circular DNA (cccDNA). To identify host factors involved in cccDNA formation, we developed an unbiased approach to discover proteins involved in cccDNA formation by precipitating nuclear rcDNA from induced HepAD38 cells and identifying the coprecipitated proteins by mass spectrometry. DNA damage binding protein 1 (DDB1) surfaced as a hit, coinciding with our previously reported short hairpin RNA (shRNA) screen in which shRNA-DDB1 in HepDES19 cells reduced cccDNA production. DDB1 binding to nuclear rcDNA was confirmed in HepAD38 cells via ChIP-qPCR. DDB1 and DNA damage binding protein 2 (DDB2) form the UV-DDB complex, and the latter senses DNA damage to initiate the global genome nucleotide excision repair (GG-NER) pathway. To investigate the role of the DDB complex in cccDNA formation, DDB2 was knocked out in HepAD38 and HepG2-NTCP cells. In both knockout cell lines, cccDNA formation was stunted significantly, and in HepG2-NTCP-DDB2 knockout cells, downstream indicators of cccDNA such as HBV RNA, HBcAg, and HBeAg were similarly reduced. Knockdown of DDB2 in HBV-infected HepG2-NTCP cells and primary human hepatocytes (PHH) also resulted in cccDNA reduction. Transcomplementation of wild-type DDB2 in HepG2-NTCP-DDB2 knockout cells rescued cccDNA formation and its downstream indicators. However, ectopic expression of DDB2 mutants deficient in DNA binding, DDB1 binding, or ubiquitination failed to rescue cccDNA formation. Our study thus suggests an integral role of UV-DDB, specifically DDB2, in the formation of HBV cccDNA. IMPORTANCE Serving as a key viral factor for chronic hepatitis B virus (HBV) infection, HBV covalently closed circular DNA (cccDNA) is formed in the cell nucleus from viral relaxed circular DNA (rcDNA) by hijacking host DNA repair machinery. Previous studies have identified several host DNA repair factors involved in cccDNA formation through hypothesis-driven research with some help from RNA interference (RNAi) screening and/or biochemistry approaches. To enrich the landscape of tools for discovering host factors responsible for rcDNA-to-cccDNA conversion, we developed an rcDNA immunoprecipitation paired mass spectrometry assay, which allowed us to pull down nuclear rcDNA in its transitional state to cccDNA and observe the associated host factors. From this assay, we discovered a novel relationship between the UV-DDB complex and cccDNA formation, providing a proof of concept for a more direct discovery of novel HBV DNA-host interactions that can be exploited to develop new cccDNA-targeting antivirals.


Assuntos
DNA Circular/metabolismo , DNA Viral/metabolismo , Proteínas de Ligação a DNA/metabolismo , Vírus da Hepatite B/fisiologia , Linhagem Celular , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Replicação do DNA , Proteínas de Ligação a DNA/genética , Antígenos da Hepatite B/metabolismo , Vírus da Hepatite B/metabolismo , Humanos , Ligação Proteica , Proteômica , RNA Viral/metabolismo , Ubiquitinação , Replicação Viral
6.
Clin Gastroenterol Hepatol ; 20(6): 1343-1353.e16, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34500103

RESUMO

BACKGROUND & AIMS: Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC. METHODS: The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort. RESULTS: A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26-0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28-0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28-0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00-1.67). CONCLUSIONS: This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.


Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Antígenos da Hepatite B/uso terapêutico , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/etiologia , Pessoa de Meia-Idade
7.
Front Immunol ; 12: 734246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691041

RESUMO

T-cell therapy with T cells that are re-directed to hepatitis B virus (HBV)-infected cells by virus-specific receptors is a promising therapeutic approach for treatment of chronic hepatitis B and HBV-associated cancer. Due to the high number of target cells, however, side effects such as cytokine release syndrome or hepatotoxicity may limit safety. A safeguard mechanism, which allows depletion of transferred T cells on demand, would thus be an interesting means to increase confidence in this approach. In this study, T cells were generated by retroviral transduction to express either an HBV-specific chimeric antigen receptor (S-CAR) or T-cell receptor (TCR), and in addition either inducible caspase 9 (iC9) or herpes simplex virus thymidine kinase (HSV-TK) as a safety switch. Real-time cytotoxicity assays using HBV-replicating hepatoma cells as targets revealed that activation of both safety switches stopped cytotoxicity of S-CAR- or TCR-transduced T cells within less than one hour. In vivo, induction of iC9 led to a strong and rapid reduction of transferred S-CAR T cells adoptively transferred into AAV-HBV-infected immune incompetent mice. One to six hours after injection of the iC9 dimerizer, over 90% reduction of S-CAR T cells in the blood and the spleen and of over 99% in the liver was observed, thereby limiting hepatotoxicity and stopping cytokine secretion. Simultaneously, however, the antiviral effect of S-CAR T cells was diminished because remaining S-CAR T cells were mostly non-functional and could not be restimulated with HBsAg. A second induction of iC9 was only able to deplete T cells in the liver. In conclusion, T cells co-expressing iC9 and HBV-specific receptors efficiently recognize and kill HBV-replicating cells. Induction of T-cell death via iC9 proved to be an efficient means to deplete transferred T cells in vitro and in vivo containing unwanted hepatotoxicity.


Assuntos
Transferência Adotiva , Caspase 9/biossíntese , Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/terapia , Linfócitos T/transplante , Transferência Adotiva/efeitos adversos , Animais , Caspase 9/genética , Morte Celular , Linhagem Celular , Técnicas de Cocultura , Citocinas/metabolismo , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Indução Enzimática , Feminino , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/imunologia , Hepatite B Crônica/metabolismo , Hepatite B Crônica/virologia , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Simplexvirus/enzimologia , Simplexvirus/genética , Linfócitos T/enzimologia , Linfócitos T/imunologia , Linfócitos T/patologia , Timidina Quinase/genética , Timidina Quinase/metabolismo , Transdução Genética
8.
Cancer Control ; 28: 10732748211039758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34569320

RESUMO

BACKGROUND AND AIMS: This retrospective study aimed to investigate the impact of positive hepatitis B core antibody (anti-HBc) and metabolic disorders on clinical characteristics of hepatocellular carcinoma (HCC) patients in an HBV-endemic area. METHODS: A total of 1950 consecutive patients newly diagnosed with HCC between 2002 and 2015 were included. Patient records were reviewed. We compared non-viral and non-alcoholic HCC patients with other etiological groups for HCC. In addition, we compared HCC patients with negative hepatitis B surface antigen (HBsAg) and positive anti-HBc to those with negative HBsAg and negative anti-HBc, and to those with HBV. RESULTS: The prevalence of non-viral and non-alcoholic HCC increased from 7% in 2002-2011 to 12% in 2012-2015. The proportion of non-viral and non-alcoholic HCC gradually increased with age. Patients with non-viral and non-alcoholic HCC exhibited higher rates of metabolic disorders and preserved liver function. The rate of anti-HBc positivity was similarly high in all HCC etiological groups. The clinical features of HCC patients with negative HBsAg and positive anti-HBc were similar to those with negative HBsAg and negative anti-HBc, but significantly different from those with HBV HCC. Regarding tumor characteristics, patients in the non-viral and non-alcoholic HCC group had more advanced stages of tumors (mUICC stage III-V and BCLC stage C/D). There was no significant difference in overall survival among the patient groups. The presence of anti-HBc did not affect patient survival. CONCLUSION: Patients with non-viral and non-alcoholic HCC had a relatively high prevalence of metabolic disorders and preserved liver function. However, they had advanced tumor stage compared to patients from other etiological groups. Anti-HBc positivity did not affect the clinical characteristics or prognosis of non-HBV HCC patients in this study.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Anticorpos Anti-Hepatite B/imunologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Doenças Metabólicas/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/imunologia , Feminino , Antígenos da Hepatite B , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco
9.
Front Immunol ; 12: 691766, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456908

RESUMO

About 250 million people worldwide are chronically infected with Hepatitis B virus (HBV), contributing to a large burden on public health. Despite the existence of vaccines and antiviral drugs to prevent infection and suppress viral replication respectively, chronic hepatitis B (CHB) cure remains a remote treatment goal. The viral persistence caused by HBV is account for the chronic infection which increases the risk for developing liver cirrhosis and hepatocellular carcinoma (HCC). HBV virion utilizes various strategies to escape surveillance of host immune system therefore enhancing its replication, while the precise mechanisms involved remain elusive. Accumulating evidence suggests that the proteins encoded by HBV (hepatitis B surface antigen, hepatitis B core antigen, hepatitis B envelope antigen, HBx and polymerase) play an important role in viral persistence and liver pathogenesis. This review summarizes the major findings in functions of HBV encoding proteins, illustrating how these proteins affect hepatocytes and the immune system, which may open new venues for CHB therapies.


Assuntos
Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Proteínas Virais/imunologia , Animais , DNA Polimerase Dirigida por DNA/imunologia , Hepatite B/complicações , Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Humanos , Fígado/patologia , Hepatopatias/etiologia
10.
World J Gastroenterol ; 27(25): 3790-3801, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34321844

RESUMO

Hepatitis B virus (HBV) infection is a public health threat that affects 257 million people worldwide and can progress to liver cirrhosis, liver failure, and hepatocellular carcinoma. The HBV antigen- induced adaptive immune response plays an important role in HBV clearance. Immune repertoire sequencing (IRS) has been used to investigate the molecular mechanisms behind the immune system, find novel ways to treat HBV infection, and evaluate the genetic responses and immune characteristics of individuals infected by HBV or immunized by HBV vaccine. This review summarizes the human immune repertoire analysis methodology, and the application of the IRS in the prediction of HBV infection progression, treatment, and vaccination.


Assuntos
Hepatite B Crônica , Hepatite B , Neoplasias Hepáticas , Hepatite B/terapia , Antígenos da Hepatite B , Vacinas contra Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/terapia , Humanos
11.
J Hepatol ; 75(5): 1058-1071, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34171437

RESUMO

BACKGROUND & AIMS: Current antiviral therapies control but rarely eliminate HBV, leaving chronic HBV carriers at risk of developing hepatocellular carcinoma (HCC). Lacking or dysfunctional virus-specific adaptive immunity prevents control of HBV and allows the virus to persist. Restoring antiviral T-cell immunity could lead to HBV elimination and cure of chronically infected patients. METHODS: We constructed bispecific T-cell engager antibodies that are designed to induce antiviral immunity through simultaneous binding of HBV envelope proteins (HBVenv) on infected hepatocytes and CD3 or CD28 on T cells. T-cell engager antibodies were employed in co-cultures with healthy donor lymphocytes and HBV-infected target cells. Activation of the T-cell response was determined by detection of pro-inflammatory cytokines, effector function (by cytotoxicity) and antiviral effects. To study in vivo efficacy, immune-deficient mice were transplanted with HBVenv-positive and -negative hepatoma cells. RESULTS: The 2 T-cell engager antibodies synergistically activated T cells to become polyfunctional effectors that in turn elicited potent antiviral effects by killing infected cells and in addition controlled HBV via non-cytolytic, cytokine-mediated antiviral mechanisms. In vivo in mice, the antibodies attracted T cells specifically to the tumors expressing HBVenv resulting in T-cell activation, tumor infiltration and reduction of tumor burden. CONCLUSION: This study demonstrates that the administration of HBVenv-targeting T-cell engager antibodies facilitates a robust T-cell redirection towards HBV-positive target cells and provides a feasible and promising approach for the treatment of chronic viral hepatitis and HBV-associated HCC. LAY SUMMARY: T-cell engager antibodies are an interesting, novel therapeutic tool to restore immunity in patients with chronic hepatitis B. As bispecific antibodies, they bind envelope proteins on the surface of the hepatitis B virus (HBV) and CD3 or CD28 on T cells. This way, they induce a potent antiviral and cytotoxic T-cell response that leads to the elimination of HBV-positive cells. These bispecific T-cell engager antibodies are exciting therapeutic candidates for chronic hepatitis B and HBV-associated hepatocellular carcinoma.


Assuntos
Antígenos da Hepatite B/sangue , Hepatite B/sangue , Linfócitos T/imunologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Citometria de Fluxo/estatística & dados numéricos , Hepatite B/epidemiologia , Antígenos da Hepatite B/análise , Antígenos da Hepatite B/metabolismo , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Camundongos , Estatísticas não Paramétricas , Linfócitos T/fisiologia
13.
Hosp Pract (1995) ; 49(3): 221-228, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33663301

RESUMO

OBJECTIVES: To assess the seroprevalence of Hepatitis B (HBV), Hepatitis C (HCV), and Human Immunodeficiency Virus (HIV) among newly admitted health track students in a large university in the Eastern Province of Saudi Arabia, and determine the students' immunity against HBV, and bloodborne viral infection risk factors or practices among them. METHODS: Information about the 1145 students, vaccination history, and exposure to bloodborne viral infections risk factors/practices were collected using a structured questionnaire during August 2020. The results of serological data were obtained from students' electronic files. RESULTS: All students tested negative for HBV, HCV, and HIV infections. The seroprevalence of positivity against HBV was 25.8%, and the frequencies of students with protective levels of anti-HBV were inversely related to their age. The majority (70.8%) of students had 1 or 2 identifiable risk factors for bloodborne diseases, and the most frequent risk factor was history of dental intervention. Female students were more than four-times likely to be in the high-risk group for bloodborne infections than males (OR = 4.4; 95% CI: 3.3-5.9). Being from the Central Province of Saudi Arabia (OR = 1.9; 95% CI: 1.2-3.1) and having a mother's educational level of master or doctorate (OR = 3.0; 95% CI: 1.3-6.7) were found to be independent predictors of being in the high-risk group. On the other hand, having a family member in the healthcare field was found as a predictor of being in the low-risk group for bloodborne diseases (OR = 0.7; 95% CI: 0.5-0.9). CONCLUSION: About three-fourth of students in this study were susceptible to HBV. Our findings stress the need to develop policies to raise awareness regarding bloodborne infectious diseases, in addition to expanding access to HBV vaccination for healthcare staff, especially in older ages.


Assuntos
Soropositividade para HIV/diagnóstico , Hepatite B/diagnóstico , Hepatite C/diagnóstico , Estudantes de Ciências da Saúde/estatística & dados numéricos , Adulto , Estudos Transversais , Feminino , Anticorpos Anti-HIV/sangue , Soropositividade para HIV/epidemiologia , Hepatite B/epidemiologia , Antígenos da Hepatite B/sangue , Hepatite C/epidemiologia , Anticorpos Anti-Hepatite C/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Arábia Saudita , Estudos Soroepidemiológicos , Adulto Jovem
14.
J Steroid Biochem Mol Biol ; 210: 105854, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33631373

RESUMO

Hepatitis B virus (HBV) infection is a global health problem with different immunological phases and therapeutic approaches. The serological condition of inactive carrier (IC) was recently well defined as a clinical and virological stable status, in which specific treatment is usually deferred, while the active chronic hepatitis B (CHB) condition requires an immediate treatment strategy. Recently, a possible broad antiviral effect of oxysterols, in particular 25-hydroxycholesterol (25OHC) and 27-hydroxycholesterol (27OHC), was observed, as most likely linked to the positive modulation of innate immunity, but no clear evidence is available about their possible role in chronic HBV infection. Thus, we examined the relationship between the plasma levels of oxysterols and the disease condition of 40 HBV patients, without treatment at the start of the study. Of these, 33 were ICs and 7 were active CHB subjects. A marked reduction of 25OHC and 27OHC plasma levels was detectable in all active CHB recruited patients, while the plasma values observed in ICs all remained within the physiological range. No difference was observed between the two groups of patients with regard to the plasma levels of 24-hydroxycholesterol (24OHC). Further, the plasma level of 27OHC ≥ 140 µg/L was shown to be predictive of an inactive carrier status. This cohort study points to 27OHC as a good candidate biomarker to differentiate active and inactive CHB status. An increasing bulk of research reports is supporting the very likely contribution of this oxysterol to the immunological control of chronic hepatitis B.


Assuntos
Portador Sadio/sangue , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Hidroxicolesteróis/sangue , Adulto , Biomarcadores/sangue , Portador Sadio/virologia , Técnicas de Imagem por Elasticidade , Feminino , Genótipo , Antígenos da Hepatite B/sangue , Vírus da Hepatite B/genética , Hepatite B Crônica/imunologia , Hepatite B Crônica/fisiopatologia , Humanos , Fígado/fisiopatologia , Fígado/virologia , Masculino , Estudos Prospectivos
15.
Cell Immunol ; 362: 104283, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33548734

RESUMO

The natural course of chronic hepatitis B virus (HBV) infections follows distinct clinical disease phases, characterized by fluctuating levels of serum HBV DNA and ALT. The immune cells and their features that govern these clinical disease transitions remain unknown. In the current study, we performed RNA sequencing on purified B cells from blood (n = 42) and liver (n = 10) of healthy controls and chronic HBV patients. We found distinct gene expression profiles between healthy controls and chronic HBV patients, as evidenced by 190 differentially expressed genes (DEG), but also between the clinical phenotypes of a chronic HBV infection (17-110 DEG between each phase). Numerous immune pathways, including the B cell receptor pathway were upregulated in liver B cells when compared to peripheral B cells. Further investigation of the detected DEG suggested an activation of B cells during HBeAg seroconversion and an active regulation of B cell signalling in the liver.


Assuntos
Linfócitos B/imunologia , Antígenos da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Adulto , Linfócitos B/fisiologia , DNA Viral , Progressão da Doença , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/fisiopatologia , Humanos , Fígado/imunologia , Fígado/fisiopatologia , Fígado/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise de Sequência de RNA/métodos , Transcriptoma/genética
16.
STAR Protoc ; 2(1): 100264, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33490980

RESUMO

In T cell-based cancer immunotherapy, tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) can specifically target tumor Ags on malignant cells. This promising approach drove us to adopt this strategy of T cell transfer (ACT)-based immunotherapy for chronic viral infections. Here, we describe the generation of hepatitis B virus (HBV) Ag-specific CTLs from induced pluripotent stem cells (iPSCs), i.e., iPSC-CTLs. Ag-specific iPSC-CTLs can target HBV Ag+ cells and infiltrate into the liver to suppress HBV replication in a murine model. For complete details on the use and execution of this protocol, please refer to Haque et al. (2020).


Assuntos
Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Hepatite B/imunologia , Hepatite B/terapia , Humanos , Imunoterapia Adotiva , Camundongos
17.
Microbiol Immunol ; 65(5): 189-203, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33491806

RESUMO

Viruses utilize cellular proteins to mediate their life cycle. However, the hepatitis B virus (HBV) life cycle is still mysterious and remains to be elucidated. Here, GRP78/BiP/HSPA5, a 78 kDa glucose-regulated protein, was identified as a preS2 interacting protein. Pulldown assay showed the interaction of glucose-regulated protein 78 (GRP78) with both the preS2 domain-containing large S and middle S proteins expressed in a human hepatocellular cell line. The immunofluorescence studies revealed that the preS2 colocalized with GRP78. Interestingly, it was found that preS2 specifically bound to the ATPase domain of GRP78. To understand how GRP78 plays a role in HBV infection, stably GRP78-expressing cells were established, which promoted HBV infectivity and replication. In contrast, knockdown of GRP78 changed the HBV antigen secretion but not the viral DNA amplification. Taken together, these results suggest that GRP78 should interact with preS2 via the ATPase domain and modulate both the HBV infectivity and HBV antigen secretion.


Assuntos
Proteínas de Choque Térmico/fisiologia , Antígenos da Hepatite B , Vírus da Hepatite B , Hepatite B , Linhagem Celular , DNA Viral , Chaperona BiP do Retículo Endoplasmático , Vírus da Hepatite B/patogenicidade , Humanos
18.
JCI Insight ; 6(3)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33400688

RESUMO

Hepatitis B virus-specific (HBV-specific) CD8+ T cells fail to acquire effector functions after priming in the liver, but the molecular basis for the dysfunction is poorly understood. By comparing the gene expression profile of intrahepatically primed, dysfunctional HBV-specific CD8+ T cells with that of systemically primed, functional effector counterparts, we found that the expression of interferon-stimulated genes (ISGs) is selectively suppressed in the dysfunctional CD8+ T cells. The ISG suppression was associated with impaired phosphorylation of STAT1 in response to IFN-α treatment. Importantly, a strong induction of type I interferons (IFN-Is) in the liver facilitated the functional differentiation of intrahepatically primed HBV-specific CD8+ T cells in association with the restoration of ISGs' expression in the T cells. These results suggest that intrahepatic priming suppresses IFN-I signaling in CD8+ T cells, which may contribute to the dysfunction. The data also suggest a therapeutic value of the robust induction of intrahepatic IFN-Is for the treatment of chronic HBV infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Vírus da Hepatite B/imunologia , Interferon Tipo I/biossíntese , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Antígenos da Hepatite B/genética , Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Tolerância Imunológica/genética , Interferon Tipo I/genética , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transcriptoma
19.
Gut ; 70(2): 357-369, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32229546

RESUMO

OBJECTIVE: Vaccination against hepatitis B virus (HBV) confers protection from subsequent infection through immunological memory that is traditionally considered the domain of the adaptive immune system. This view has been challenged following the identification of antigen-specific memory natural killer cells (mNKs) in mice and non-human primates. While the presence of mNKs has been suggested in humans based on the expansion of NK cells following pathogen exposure, evidence regarding antigen-specificity is lacking. Here, we demonstrate the existence of HBV-specific mNKs in humans after vaccination and in chronic HBV infection. DESIGN: NK cell responses were evaluated by flow cytometry and ELISA following challenge with HBV antigens in HBV vaccinated, non-vaccinated and chronic HBV-infected individuals. RESULTS: NK cells from vaccinated subjects demonstrated higher cytotoxic and proliferative responses against autologous hepatitis B surface antigen (HBsAg)-pulsed monocyte-derived dendritic cells (moDCs) compared with unvaccinated subjects. Moreover, NK cell lysis of HBsAg-pulsed moDCs was significantly higher than that of hepatitis B core antigen (HBcAg)-pulsed moDCs (non-vaccine antigen) or tumour necrosis factor α-activated moDCs in a NKG2D-dependent manner. The mNKs response was mediated by CD56dim NK cells coexpressing CD57, CD69 and KLRG1. Further, mNKs from chronic hepatitis B patients exhibited greater degranulation against HBcAg-pulsed moDCs compared with unvaccinated or vaccinated patients. Notably, mNK activity was negatively correlated with HBV DNA levels. CONCLUSIONS: Our data support the presence of a mature mNKs following HBV antigen exposure either through vaccination or infection. Harnessing these antigen specific, functionally active mNKs provides an opportunity to develop novel treatments targeting HBV in chronic infection.


Assuntos
Vacinas contra Hepatite B/imunologia , Hepatite B/imunologia , Memória Imunológica/imunologia , Células Matadoras Naturais/imunologia , Imunidade Adaptativa/imunologia , Anticorpos Antivirais/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Antígenos da Hepatite B/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade
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