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1.
Immunity ; 54(9): 2089-2100.e8, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34469774

RESUMO

Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8+ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Interleucina-2/imunologia , Macrófagos do Fígado/imunologia , Animais , Hepatite B/imunologia , Tolerância Imunológica/imunologia , Camundongos , Camundongos Transgênicos
2.
Viruses ; 13(7)2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34372550

RESUMO

Persistent hepatitis B virus (HBV) infection remains a serious medical problem worldwide, with an estimated global burden of 257 million carriers. Prophylactic and therapeutic interventions, in the form of a vaccine, immunomodulators, and nucleotide and nucleoside analogs, are available. Vaccination, however, offers no therapeutic benefit to chronic sufferers and has had a limited impact on infection rates. Although immunomodulators and nucleotide and nucleoside analogs have been licensed for treatment of chronic HBV, cure rates remain low. Transcription activator-like effector nucleases (TALENs) designed to bind and cleave viral DNA offer a novel therapeutic approach. Importantly, TALENs can target covalently closed circular DNA (cccDNA) directly with the potential of permanently disabling this important viral replicative intermediate. Potential off-target cleavage by engineered nucleases leading to toxicity presents a limitation of this technology. To address this, in the context of HBV gene therapy, existing TALENs targeting the viral core and surface open reading frames were modified with second- and third-generation FokI nuclease domains. As obligate heterodimers these TALENs prevent target cleavage as a result of FokI homodimerization. Second-generation obligate heterodimeric TALENs were as effective at silencing viral gene expression as first-generation counterparts and demonstrated an improved specificity in a mouse model of HBV replication.


Assuntos
Vírus da Hepatite B/genética , Hepatite B/tratamento farmacológico , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Animais , Animais não Endogâmicos , Antivirais/uso terapêutico , Linhagem Celular , Vírus de DNA/genética , DNA Circular , DNA Viral/genética , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Modelos Animais de Doenças , Endonucleases/genética , Feminino , Terapia Genética/métodos , Células HEK293 , Células Hep G2 , Hepatite B/genética , Hepatite B/imunologia , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Camundongos , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/uso terapêutico , Replicação Viral/genética
3.
Medicine (Baltimore) ; 100(29): e26665, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398029

RESUMO

BACKGROUND: Data on the epidemiology characteristics of hepatitis B surface antibodies (anti-HBs) are lacking among central southern undeveloped areas of China, especially for young adults. This study aims to demonstrate the sero-epidemiology characteristics of HBsAb among young adults. AIMS: The aim of this study is to demonstrate the epidemiological characteristics in prevalence of serum anti-HBs in college students of a university in Hunan Province, China. METHODS: Data were derived from the health records (including serum HBsAb data) among freshmen of a university from 2017 to 2019 in Hunan Province, China. RESULTS: A total of 13,426 freshmen with complete data who were born in Hunan Province were collected. The 3-year total prevalence of anti-HBs in freshmen was 44.75% with no statistically significant sex difference, the prevalence of anti-HBs is 46.93%, 53.13%, and 34.79% for 2017, 2018, and 2019, respectively. There are significant geographic differences of prevalence of anti-HBs in freshmen from different areas. The lowest prevalence of anti-HBs was 31.80% in freshmen from Xiangtan, and the highest prevalence of anti-HBs was 53.10% in freshmen from Yongzhou. CONCLUSION: The prevalence of serum anti-HBs among the freshmen in Hunan from 2017 to 2019 is much lower than the average national level, and the prevalence in 2019 is significantly lower than that in 2017 and 2019. There are significant differences in different time and areas of the prevalence of anti-HBs. There is a necessity to carry out area-specific intensive immunization plan in a timely manner among young population in Hunan Province, China.


Assuntos
Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Hepatite B/epidemiologia , Adolescente , Adulto , China/epidemiologia , Feminino , Hepatite B/imunologia , Humanos , Masculino , Prevalência , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Estudos Soroepidemiológicos , Universidades , Vacinação , Adulto Jovem
4.
Front Immunol ; 12: 638678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335561

RESUMO

Background: Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for hematologic malignancies and is predicted to experience widespread use in the near future. However, not all risks associated with this novel approach are well defined. There are few data in the risk of HBV reactivation and limited experience in management in patients with resolved HBV infection who undergo CAR-T cell therapy. Methods: We performed a post-hoc analysis of a prospective clinical trial of anti-CD19 CAR-T (CART19) cell therapy in patients with relapsed or refractory (r/r) B-cell malignancies, and aimed at exploring the actual risk of HBV reactivation in a cohort of patients with resolved HBV infection receiving CART19 cell therapy in the absence of antiviral prophylaxis. Results: In this study, we investigated the risk of HBV reactivation after CART19 cell therapy in 30 consecutive patients with B-cell malignancies and resolved HBV infection without antiviral prophylaxis, in the Tongji Hospital of Tongji University. In this cohort, two patients developed HBV reactivation 2 months and 14 months after CAR-T cell infusion, respectively, the latter of whom developed severe hepatitis. These findings showed that the incidence of HBV reactivation was 6.67% (95% CI, 0.8-22.1). Specifically, none of the 21 patients who were HBsAb positive (0.0%) versus two of nine patients who were HBsAb negative (22.2%) experienced HBV reactivation (p = 0.03), suggesting HbsAb seronegativity at baseline is a possible risk factor in this population. Although use of tocilizumab or corticosteroids has been associated with increased risk of HBV reactivation, none of the patients who received these agents had HBV reactivation in this study. Conclusion: This is the first and largest study to assess the true incidence of HBV reactivation in patients with resolved HBV infection receiving CART19 cell therapy without antiviral prophylaxis. This study highlights that this population are at risk of developing HBV reactivation and indicates that close monitoring of HBV DNA is required in the absence of antiviral prophylaxis. In addition, antiviral prophylaxis is recommended in the HBsAb-negative subpopulation.


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/fisiologia , Hepatite B/terapia , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Adolescente , Adulto , Antígenos CD19/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Hepatite B/imunologia , Humanos , Lactente , Linfoma de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Ativação Viral , Adulto Jovem
5.
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
6.
Viruses ; 13(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34452505

RESUMO

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


Assuntos
Modelos Animais de Doenças , Tupaia , Viroses , Infecções por Adenoviridae/imunologia , Infecções por Adenoviridae/virologia , Animais , COVID-19/virologia , Dengue/imunologia , Dengue/patologia , Dengue/virologia , Infecções por HIV/virologia , Hepatite B/imunologia , Hepatite B/virologia , Hepatite C/imunologia , Hepatite C/patologia , Hepatite C/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/imunologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia
7.
Cells ; 10(8)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34440630

RESUMO

Hepatitis B virus-related hepatocellular carcinoma recurrence after liver transplantation (LT) is notoriously difficult to manage and fatal. As a therapeutic option, adoptive cell therapy with HBV-specific TCR-redirected T cells could be employed to target and control relapses in these patients. However, indispensable immunosuppressive medications post-transplantation can significantly hinder the optimum efficacy of such therapy in the clinic. Here we report a new class of Armored TCR T cells which are able to attack recurrent cancer cells in liver transplanted recipients, while temporarily evading immunosuppressant drugs. We believe this strategy could open up new opportunities for treating pathologies under immunosuppressant treatment.


Assuntos
Carcinoma Hepatocelular/terapia , Vírus da Hepatite B/patogenicidade , Hepatite B/virologia , Imunoterapia Adotiva , Neoplasias Hepáticas/terapia , Transplante de Fígado/efeitos adversos , Recidiva Local de Neoplasia/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/transplante , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Terapia Genética , Hepatite B/complicações , Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/virologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/virologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
8.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299262

RESUMO

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.


Assuntos
Antígenos de Superfície da Hepatite B/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/metabolismo , Adulto , DNA Viral/metabolismo , Feminino , Hepatite B/imunologia , Hepatite B/metabolismo , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/imunologia , Hepatite B Crônica/metabolismo , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Carga Viral , Replicação Viral
9.
Cells ; 10(6)2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199483

RESUMO

Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells; however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/patologia , Feminino , Hepatite B/imunologia , Hepatite B/patologia , Vírus da Hepatite B/imunologia , Humanos , Células Matadoras Naturais/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade
10.
PLoS One ; 16(7): e0253752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34197516

RESUMO

BACKGROUND: Despite completion of the vaccine schedule for hepatitis B virus (HBV), children may display levels of HBV surface antibodies (anti-HBs) that are considered inadequate for sufficient protection (<10 IU/L). AIMS: Our aim was to investigate if age and gap time between HBV vaccine doses may negatively affect the levels of anti-HBs in children, and if these relationships are modified by sex. METHODS: In a high-endemic HBV region of the western Brazilian Amazon we enrolled children who had completed the HBV vaccine schedule. All children underwent analysis of anti-HBs and a clinical examination. RESULTS: We included 522 children (mean age 4.3 ± 0.8 years; 50% male). Median anti-HBs was 28.4 [interquartile range (IQR) 5.4 to 128.6] IU/L and 32% had anti-HBs <10 IU/L. The median gap time from last to preceding dose was 2.4 [IQR 2.1 to 3.3] months. Levels of anti-HBs decreased with higher age (-42% per year increase [95%CI -56% to -24%], p<0.001), but not with longer gap time (+23% per month increase [95%CI -16% to +62%], p = 0.249). After adjusting for relevant confounders, gap time became significant (p = 0.032) and age remained a significant predictor of anti-HBs (p<0.001). CONCLUSION: One third of assessed children displayed anti-HBs <10 IU/L. Levels of anti-HBs decreased with higher age and increased with longer gap time between the last two doses.


Assuntos
Anticorpos Anti-Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B/imunologia , Esquemas de Imunização , Fatores Etários , Brasil , Pré-Escolar , Estudos Transversais , Doenças Endêmicas/prevenção & controle , Feminino , Hepatite B/sangue , Hepatite B/prevenção & controle , Hepatite B/virologia , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/imunologia , Humanos , Masculino , Vacinação em Massa , Testes Sorológicos/estatística & dados numéricos , Fatores de Tempo
11.
Curr Opin Virol ; 49: 194-202, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34242953

RESUMO

Hepatitis B virus (HBV) chronically infects 257 million people and is one of the most important liver diseases worldwide. A unique feature of HBV infection in humans is that viral clearance heavily depends on the age at exposure. Recent studies demonstrated that the virus takes advantage of immature innate immunity, especially hepatic macrophages, and not-yet-stabilized gut microbiota in early life to establish a chronic infection. The liver contains resident and infiltrating myeloid cells involved in immune responses to pathogens. They influence both innate and adaptive sectors of the immune system and their interplay with HBV has only been noticed recently. Here, we discuss how interactions between gut microbiota and hepatic macrophages influence the outcomes of HBV infection. Understanding the underlying mechanism would pave the way for the treatment of chronic HBV infection.


Assuntos
Envelhecimento , Microbioma Gastrointestinal/fisiologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B/imunologia , Imunidade Inata , Animais , Vírus da Hepatite B/fisiologia , Humanos , Fígado/imunologia , Macrófagos/imunologia
12.
Front Immunol ; 12: 684424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113355

RESUMO

Whether hepatitis B virus (HBV) activates or represses innate immunity continues to be debated. Toll-like receptor (TLR) 2 has been identified to recognize HBV particles in human hepatocytes. The Hippo pathway, known for growth control, is suggested to play a vital role in immune regulation. Here, molecular interactions between HBV-triggered TLR signaling and the Hippo pathway were comprehensively investigated. Reanalysis of GSE69590 data, in which human hepatocytes have been treated with cell culture-derived HBV particles, identified changes in Hippo and NF-κB signaling. Immunocytochemical staining and western blotting revealed time-dependent nuclear translocation of YAP and NF-κB in HBV-exposed primary human and murine hepatocytes (PMH). Analysis of PMH isolated from MyD88- or IRAK4-deficient mice and the inhibition of TLR2 and MST1/2 in vitro confirmed the relation between TLR2 and Hippo signaling in HBV-induced immunity. Loss and gain of function experiments implied that Hippo-downstream effector YAP directly regulated IκBα expression. Functional investigations confirmed the regulation of Nfkbia promoter activity by the YAP/TEAD4 transcription factor complex. Administration of TLR ligands to mice highlighted the relevance of the TLR2-MyD88-IRAK4-Hippo axis in hepatic immunity. Interestingly, reanalysis of gene expression pattern in liver biopsies of patients chronically infected with HBV (GSE83148, GSE65359) indicated an activation of TLR2 and however, an MST1-dominated Hippo control in the immune clearance phase of patients with chronic HBV infection. We demonstrated that MyD88-dependent TLR signaling activates NF-κB and Hippo signaling, with YAP prompting the IκBα-mediated negative feedback, alongside NF-κB. Imbalance between immune induction and Hippo activation may have implications for the safety of novel HBV cure strategies interfering with pathogen recognition receptors.


Assuntos
Vírus da Hepatite B/imunologia , Hepatite B/imunologia , Imunidade Inata , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Hepatite B/genética , Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Fatores de Transcrição
13.
Front Immunol ; 12: 661204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995383

RESUMO

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Epigênese Genética/imunologia , Vírus da Hepatite B/imunologia , Hepatite B/imunologia , Neoplasias Hepáticas/imunologia , MicroRNAs/imunologia , Transativadores/imunologia , Proteínas Virais Reguladoras e Acessórias/imunologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Regulação Neoplásica da Expressão Gênica/imunologia , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virologia , MicroRNAs/genética , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
14.
Viruses ; 13(3)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810128

RESUMO

BACKGROUND: Interaction between host transcription factors (TFs) and the viral genome is fundamental for hepatitis B virus (HBV) gene expression regulation. Additionally, the distinct interaction of the TFs' network with the HBV genome determines the regulatory effect outcome. Hence, different HBV genotypes and their variants may display different viral replication/transcription regulation. Due to the lack of an efficient infection model suitable for all HBV genotypes, the hepatoma cell transfection model is primarily used in studies involving non-D HBV genotypes and variants. METHODS: We explored the transcriptome profile of host TFs with a regulatory effect on HBV in eight liver-derived cell lines in comparison with primary human hepatocytes (PHH). We further analyzed the suitability of these models in supporting HBV genotype B replication/transcription. RESULTS: Among studied models, HC-04, as a result of the close similarity of TFs transcriptome profile to PHH and the interaction of specific TFs including HNF4α and PPARα, showed the highest efficiency in regard to viral replication and antigen production. The absence of TFs expression in L02 transfection model resulted in its inefficiency in HBV replication/transcription. CONCLUSION: These observations help to better design studies on regulatory mechanisms involving non-D HBV genotypes and variants' gene expression and the development of more efficient therapeutical approaches.


Assuntos
Vírus da Hepatite B , Hepatite B , Fatores de Transcrição/imunologia , Proteínas Virais/imunologia , Linhagem Celular , Regulação Viral da Expressão Gênica , Genoma Viral , Hepatite B/imunologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatócitos , Interações entre Hospedeiro e Microrganismos , Humanos , Replicação Viral
15.
Trop Med Int Health ; 26(8): 882-894, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33860608

RESUMO

OBJECTIVE: Previous reports show conflicting results regarding hepatitis B virus (HBV) vaccine efficacy in Hepatitis C virus (HCV) infected individuals and in those with isolated hepatitis B core antibodies (HBcAb). We aimed to evaluate the effectiveness of HBV vaccine and identify possible factors that may contribute to hyporesponsivness in HCV-treated patients, including those with isolated HBcAb. METHODS: We conducted a prospective study with 118 enrolled chronic HCV patients who followed a 12-week regimen of direct acting antivirals (DAAs) and were evaluated for HBV serological markers. Eventually, 98 received appropriate HBV vaccination and were assessed for response. RESULTS: A total of 57.1% were vaccine responders although only 5.1% achieved a seroprotective level of HBsAb titre. The response rate was significantly lower among treated HCV patients with isolated HBcAb [2 (5.6%) vs. 40 (64.5%) respectively]. On multivariate analysis, advanced age [OR (95% CI) = 1.09 (1.02-1.17)] and presence of isolated HbcAb [OR (95% CI) = 39.59 (7.98-196.63)] were predictors of vaccine non-response. In our cost-effectiveness models, the cost of HBV serological screening was less than the nationally adopted non-screening approach. A model ratifying reinforced vaccination in non-responder HBcAb seropositive HCV patients would incur extra cost. CONCLUSION: Hyporesponsiveness to the HBV vaccination is frequent in chronic HCV patients even after achieving SVR following DAAs. Although there is no consensus on the clinical management of patients with isolated HBcAb, our cost-effectiveness options may support decision-making for better clinical benefit and proper health investments.


Assuntos
Antivirais/uso terapêutico , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/uso terapêutico , Hepatite B/tratamento farmacológico , Hepatite C Crônica , Adolescente , Adulto , Antivirais/administração & dosagem , Custos e Análise de Custo , Estudos Transversais , Egito , Feminino , Hepatite B/economia , Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
16.
Front Immunol ; 12: 636803, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841420

RESUMO

Commensal gut microbiota protects the immune defense of extra-intestinal organs. Gut microbiota depletion by antibiotics can impair host antiviral immune responses and alter hepatitis B virus (HBV) infection outcomes. However, how gut microbiota modulates antiviral immune response in the liver remains unclear. Here, mice were treated with broad-spectrum antibiotics to deplete gut microbiota. Gut integrity was evaluated, and translocation of live commensal gut bacteria and their components into the liver was investigated. An HBV infection model was established to evaluate impairment of antiviral immune response in the liver after gut microbiota depletion. We found that gut microbiota depletion was associated with impairment of colon epithelial integrity, and live commensal gut microbiota could translocate to the liver. Further, T cell antiviral function in the liver was impaired, partially relying on enhanced PD-1 expression, and HBV immune clearance was hampered. In conclusion, gut microbiota depletion by antibiotics can impair gut barrier function and suppress T cell antiviral immune response in the liver.


Assuntos
Colo/patologia , Microbioma Gastrointestinal/fisiologia , Vírus da Hepatite B/fisiologia , Hepatite B/imunologia , Mucosa Intestinal/fisiologia , Fígado/imunologia , RNA Ribossômico 16S/genética , Linfócitos T/imunologia , Animais , Antibacterianos/administração & dosagem , Translocação Bacteriana , Células Cultivadas , Modelos Animais de Doenças , Fezes/microbiologia , Hepatite B/microbiologia , Humanos , Imunidade , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/metabolismo , Regulação para Cima , Carga Viral
17.
Mar Drugs ; 19(4)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808126

RESUMO

Hepatitis B virus (HBV) infection remains a major global health problem. It is therefore imperative to develop drugs for anti-hepatitis B with high-efficiency and low toxicity. Attracted by the observations and evidence that the symptoms of some patients from the Southern Fujian, China, suffering from hepatitis B were alleviated after daily eating an edible marine mollusk, Thais clavigera (Küster 1860) (TCK). Water-soluble polysaccharide from TCK (TCKP1) was isolated and characterized. The anti-HBV activity of TCKP1 and its regulatory pathway were investigated on both HepG2.2.15 cell line and HBV transgenic mice. The data obtained from in vitro studies showed that TCKP1 significantly enhanced the production of IFN-α, and reduced the level of HBV antigens and HBV DNA in the supernatants of HepG2.2.15 cells in a dose-dependent manner with low cytotoxicity. The result of the study on the HBV transgenic mice further revealed that TCKP1 significantly decreased the level of transaminases, HBsAg, HBeAg, and HBV DNA in the serum, as well as HBsAg, HBeAg, HBV DNA, and HBV RNA in the liver of HBV transgenic (HBV-Tg) mice. Furthermore, TCKP1 exhibited equivalent inhibitory effect with the positive control tenofovir alafenamide (TAF) on the markers above except for HBV DNA even in low dosage in a mouse model. However, the TCKP1 high-dose group displayed stronger inhibition of transaminases and liver HBsAg, HBeAg, and HBV RNA when compared with those of TAF. Meanwhile, inflammation of the liver was, by pathological observation, relieved in a dose-dependent manner after being treated with TCKP1. In addition, elevated levels of interleukin-12 (IL-12) and interferon γ (IFN-γ), and reduced level of interleukin-4 (IL-4) in the serum were observed, indicating that the anti-HBV effect of TCKP1 was achieved by potentiating immunocyte function and regulating the balance of Th1/Th2 cytokines.


Assuntos
Antivirais/farmacologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Moluscos/metabolismo , Polissacarídeos/farmacologia , Animais , Antivirais/isolamento & purificação , Citocinas/metabolismo , Modelos Animais de Doenças , Células Hep G2 , Hepatite B/imunologia , Hepatite B/metabolismo , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/metabolismo , Camundongos Transgênicos , Polissacarídeos/isolamento & purificação , Equilíbrio Th1-Th2/efeitos dos fármacos , Carga Viral
18.
Clin Immunol ; 227: 108727, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33887436

RESUMO

With the global spread of coronavirus disease 2019 (COVID-19), the important role of natural killer (NK) cells in the control of various viral infections attracted more interest, via non-specific activation, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and activating receptors, as well as specific activation, such as memory-like NK generation. In response to different viral infections, NK cells fight viruses in different ways, and different NK subsets proliferate. For instance, cytomegalovirus (CMV) induces NKG2C + CD57 + KIR+ NK cells to expand 3-6 months after hematopoietic stem cell transplantation (HSCT), but human immunodeficiency virus (HIV) induces KIR3DS1+/KIR3DL1 NK cells to expand in the acute phase of infection. However, the similarities and differences among these processes and their molecular mechanisms have not been fully discussed. In this article, we provide a summary and comparison of antiviral mechanisms, unique subset expansion and time periods in peripheral blood and tissues under different conditions of CMV, HIV, Epstein-Barr virus (EBV), COVID-19 and hepatitis B virus (HBV) infections. Accordingly, we also discuss current clinical NK-associated antiviral applications, including cell therapy and NK-related biological agents, and we state the progress and future prospects of NK cell antiviral treatment.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Interações entre Hospedeiro e Microrganismos/imunologia , Células Matadoras Naturais/imunologia , Citotoxicidade Celular Dependente de Anticorpos , COVID-19/sangue , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , HIV/imunologia , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Hepatite B/sangue , Hepatite B/imunologia , Hepatite B/virologia , Vírus da Hepatite B/imunologia , Herpesvirus Humano 4/imunologia , Humanos , SARS-CoV-2/imunologia , Receptores Toll-Like/metabolismo
19.
Mol Med ; 27(1): 32, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794763

RESUMO

BACKGROUND: An estimated 5-10 % of healthy vaccinees lack adequate antibody response following receipt of a standard three-dose hepatitis B vaccination regimen. The cellular mechanisms responsible for poor immunological responses to hepatitis B vaccine have not been fully elucidated to date. METHODS: There were 61 low responders and 56 hyper responders involved in our study. Peripheral blood samples were mainly collected at D7, D14 and D28 after revaccinated with a further dose of 20 µg of recombinant hepatitis B vaccine. RESULTS: We found low responders to the hepatitis B vaccine presented lower frequencies of circulating follicular helper T (cTfh) cells, plasmablasts and a profound skewing away from cTfh2 and cTfh17 cells both toward cTfh1 cells. Importantly, the skewing of Tfh cell subsets correlated with IL-21 and protective antibody titers. Based on the key role of microRNAs involved in Tfh cell differentiation, we revealed miR-19b-1 and miR-92a-1 correlated with the cTfh cell subsets distribution and antibody production. CONCLUSIONS: Our findings highlighted a decrease in cTfh cells and specific subset skewing contribute to reduced antibody responses in low responders.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra Hepatite B , Hepatite B/imunologia , Interleucinas/sangue , MicroRNAs , Células T Auxiliares Foliculares/imunologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Vacinação , Adulto Jovem
20.
Skinmed ; 19(1): 37-41, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33658111

RESUMO

The association between immunosuppressive therapy for dermatologic conditions and the subsequent reactivation of hepatitis B is of major medical concern. It remains a point of interest across multiple disciplines, including hepatology, dermatology, rheumatology, and infectious disease. Accordingly, we present an evidence-based practice algorithm on how best to approach a patient with presumptively cleared hepatitis B infection when anticipating the initiation of immunosuppressive therapy. This guide delineates the risk of reactivation by taking into account the immunosuppressive agent of choice and presents recommendations for antiviral prophylaxis and laboratory monitoring. Booster vaccination as a potential to decrease the risk of hepatitis B reactivation is likewise discussed. (SKINmed. 2021;19:-0).


Assuntos
Antivirais/administração & dosagem , Hepatite B/prevenção & controle , Imunossupressores/efeitos adversos , Dermatopatias/tratamento farmacológico , Algoritmos , Dermatologistas , Medicina Baseada em Evidências , Hepatite B/etiologia , Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Humanos , Imunização Secundária/métodos , Imunossupressores/administração & dosagem
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