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Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (20 December 2019) | Viewed by 47375

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Special Issue Editor

Prof. Lionel Piroth

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Guest Editor

Department of Infectiology, University Hospital, F-21000 Dijon, France
Interests: HBV; HCV; HIV; therapeutics; vaccines; immune response

Special Issue Information

Dear Colleagues,

Hepatitis viruses are a major public health concern, even though their burden is not equally distributed around the world. It was stated in 2012 that they were the 10th leading cause of death and the 16th cause of disability. Even though these viruses are basically different, resulting in different natural disease courses, they share several characteristics or determinants. Their natural disease courses and clinical outcomes are mainly determined by different virological and immunological factors. They are associated with a significant risk of acute liver failure, with fulminant courses with HAV, HBV/HDV, and HEV. HBV and HCV are non-cytopathic viruses that develop mechanisms of escape from immunological control with quantitative and functional defects of virus-specific T-cell response. This allows them to persist and cause hepatic inflammation leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). In addition, HBV is also oncogenic per se via insertional mutagenesis of cancer related genes, even though all the underlying mechanisms are not fully understood. It is also unclear whether HBV can be completely cleared from human liver. Immune responses are also critical to determine the outcome of HEV infection, which may persist in immunodepressed patients and be more severe among pregnant women. HCV, but above all HBV, can also be transmitted from mother to child, contributing to the spread of epidemics.

Thus, even though dramatic success has been reached in HCV eradication with direct antiviral agents, improving our understanding of the immunopathogenesis of these viruses remains crucial for the development of new therapeutic and preventive strategies for all these viruses, including vaccines. These are the reasons why this supplement is dedicated to immunobiology, pathogenesis, and perspectives in viral hepatitis.

Prof. Lionel Piroth
Guest Editor

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Keywords

Hepatitis virus
Acute hepatitis
Chronic hepatitis
Immune response
Pathogenesis
Cirrhosis
Hepatocellular carcinoma
Transmission
Treatment
Prevention

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Published Papers (9 papers)

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Research

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12 pages, 750 KiB

Open AccessArticle

Impact of Sustained Virological Response for Gastroesophageal Varices in Hepatitis-C-Virus-Related Liver Cirrhosis

by Yukihisa Yuri, Hiroki Nishikawa, Hirayuki Enomoto, Kazunori Yoh, Yoshinori Iwata, Yoshiyuki Sakai, Kyohei Kishino, Naoto Ikeda, Tomoyuki Takashima, Nobuhiro Aizawa, Ryo Takata, Kunihiro Hasegawa, Noriko Ishii, Takashi Nishimura, Hiroko Iijima and Shuhei Nishiguchi

J. Clin. Med. 2020, 9(1), 95; https://doi.org/10.3390/jcm9010095 - 30 Dec 2019

Cited by 13 | Viewed by 2423

Abstract

We aimed to clarify the relationship between sustained virological response (SVR) and gastroesophageal varices (GEVs) progression among hepatitis C virus (HCV)-related liver cirrhosis (LC) patients treated with interferon (IFN)-based therapies (n = 18) and direct-acting antiviral (DAA)-based therapies (n = 37), and LC patients with no SVR (n = 71) who had already developed GEVs. Factors influencing GEVs progression were also examined. During the follow-up period, GEVs progression was observed in 50 patients (39.7%). The 3-year cumulative GEVs progression rates in the DAA-SVR group, the IFN-SVR group, and the non-SVR group were 32.27%, 5.88%, and 33.76%, respectively (overall p value = 0.0108). Multivariate analysis revealed that sex (p = 0.0430), esophageal varices (EVs) F2 or more (p < 0.0001), and DAA-SVR (p = 0.0126, IFN-SVR as a reference) and non-SVR (p = 0.0012, IFN-SVR as a reference) were independent predictors for GEVs progression. The proportion of GEVs progression in patients with no or F1 EVs was significantly lower than that in patients with F2 or F3 EVs (33.9% (38/112) vs. 85.7% (12/14), p = 0.0003). In conclusion, IFN-based therapies can have a favorable impact for preventing GEVs progression in HCV-related LC patients with GEVs. Clinicians should be aware of a point of no return where SVR is no longer capable of avoiding GEVs progression. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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15 pages, 651 KiB

Open AccessArticle

Insulin Resistance Associated Disorders Pivoting Long-Term Hepatitis B Surface Antigen Decline During Entecavir Therapy

by Tien-Ching Lin, Wen-Chun Liu, Yu-Hsiang Hsu, Jia-Jhen Lin, Yen-Cheng Chiu, Hung-Chih Chiu, Pin-Nan Cheng, Chiung-Yu Chen, Ting-Tsung Chang and I-Chin Wu

J. Clin. Med. 2019, 8(11), 1892; https://doi.org/10.3390/jcm8111892 - 6 Nov 2019

Cited by 1 | Viewed by 2854

Abstract

Insulin resistance associated disorders (IRAD), including prediabetes, type 2 diabetes mellitus (T2DM), and fatty liver are significant risk factors of liver-related death in chronic hepatitis B (CHB). However, their relationship remains unclear. We aimed to evaluate how IRAD influence the kinetics of serum hepatitis B surface antigen (HBsAg) in patients with CHB during long-term entecavir treatment. We enrolled 140 patients with CHB receiving at least 3 years of consecutive entecavir treatment in this retrospective study. A linear mixed effects model was adopted to examine the effects of variables and their interaction over time on the HBsAg trajectory. Furthermore, we acquired cytokine profiles and baseline fibrosis-4 index (FIB-4) scores for in-depth analysis. The median treatment time was 6.90 (4.47–9.01) years. Multivariate analysis revealed that older patients or those with prediabetes or T2DM had a significantly slower HBsAg decline over time (p = 0.0001 and p < 0.0001, respectively). Conversely, advanced fatty liver engendered a more rapid HBsAg decrease (p = 0.001). Patients with prediabetes or T2DM possessed higher IP-10 levels six years after entecavir therapy (p = 0.013). Compared to patients without prediabetes or T2DM, diabetic patients had more unfavorable features at the baseline, especially higher FIB-4 scores. Prediabetes or T2DM delays the clearance of HBsAg, but advanced hepatic fatty change counterbalances the effect. Additionally, IRAD could cause hepatic sequelae in CHB through immune-metabolic pathways. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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18 pages, 3634 KiB

Open AccessArticle

Smoking as an Independent Risk Factor for Hepatocellular Carcinoma Due to the α7-Nachr Modulating the JAK2/STAT3 Signaling Axis

by Ching-Li Li, Yen-Kuang Lin, Hsin-An Chen, Chien-Yu Huang, Ming-Te Huang and Yu-Jia Chang

J. Clin. Med. 2019, 8(9), 1391; https://doi.org/10.3390/jcm8091391 - 5 Sep 2019

Cited by 23 | Viewed by 3283

Abstract

Background: Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective clinical therapeutic strategy for HCC. Smoking is associated with several malignant diseases including cancers. Experimental approach: However, the impact of smoking on HCC is still unresolved. Retrospectively reviewed HCC patients diagnosed between 1 January 2010 and 31 December 2015 at Taipei Medical University-Shuang Ho Hospital (Ministry of Health and Welfare). We found that smoking was associated with a poor prognosis, especially recurrence and patient survival after curative surgery using a clinicopathological analysis. Results: Our univariate and multivariate analyses showed that the α7-nicotinic acetylcholine receptor (α7-nAChR) was an oncogene and risk factor for post-resection recurrence. The α7-nAChR was overexpressed in HCC tissues compared to their non-tumor counterparts. Silencing the α7-nAChR reduced the viability of HCC cells, suppressed cellular proliferation, attenuated migration and invasion, and diminished the tumor’s sphere-formation ability, with concurrent downregulation of expression levels of the TGR5, p-JAK2, p-STAT3 (Tyr705/Ser727), RhoA, ROCK1, MMP2, and MMP9 proteins. Furthermore, a positive correlation was found between α7-nAChR and JAK2 expressions (p = 0.01) in HCC specimens, as well as their membranous co-localization. Conclusion: Together, we demonstrated that the α7-nAChR may be an independent prognosticator of the progression and prognosis of HCC patients. These findings suggest that the α7-nAChR drives the progression and recurrence of HCC through JAK2/STAT3 signaling and is a novel target for anti-HCC therapy. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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22 pages, 2675 KiB

Open AccessArticle

MicroRNA Profile of HCV Spontaneous Clarified Individuals, Denotes Previous HCV Infection

by Óscar Brochado-Kith, Alicia Gómez Sanz, Luis Miguel Real, Javier Crespo García, Pablo Ryan Murúa, Juan Macías, Joaquín Cabezas González, Jesús Troya, Juan Antonio Pineda, María Teresa Arias Loste, Victorino Díez Viñas, María Ángeles Jiménez-Sousa, Luz María Medrano de Dios, Isabel Cuesta De la Plaza, Sara Monzón Fernández, Salvador Resino García and Amanda Fernández-Rodríguez

J. Clin. Med. 2019, 8(6), 849; https://doi.org/10.3390/jcm8060849 - 14 Jun 2019

Cited by 11 | Viewed by 3740

Abstract

Factors involved in the spontaneous cleareance of a hepatitis C (HCV) infection are related to both HCV and the interaction with the host immune system, but little is known about the consequences after a spontaneous resolution. The main HCV extrahepatic reservoir is the peripheral blood mononuclear cells (PBMCs), and their transcriptional profile provides us information of innate and adaptive immune responses against an HCV infection. MicroRNAs regulate the innate and adaptive immune responses, and they are actively involved in the HCV cycle. High Throughput sequencing was used to analyze the miRNA profiles from PBMCs of HCV chronic naïve patients (CHC), individuals that spontaneously clarified HCV (SC), and healthy controls (HC). We did not find any differentially expressed miRNAs between SC and CHC. However, both groups showed similar expression differences (21 miRNAs) with respect to HC. This miRNA signature correctly classifies HCV-exposed (CHC and SC) vs. HC, with the has-miR-21-3p showing the best performance. The potentially targeted molecular pathways by these 21 miRNAs mainly belong to fatty acids pathways, although hippo signaling, extracellular matrix (ECM) interaction, proteoglycans-related, and steroid biosynthesis pathways were also altered. These miRNAs target host genes involved in an HCV infection. Thus, an HCV infection promotes molecular alterations in PBMCs that can be detected after an HCV spontaneous resolution, and the 21-miRNA signature is able to identify HCV-exposed patients (either CHC or SC). Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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Review

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19 pages, 914 KiB

Open AccessReview

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

by Gaitan Fabrice Njiomegnie, Scott A. Read, Nicole Fewings, Jacob George, Fiona McKay and Golo Ahlenstiel

J. Clin. Med. 2020, 9(4), 1030; https://doi.org/10.3390/jcm9041030 - 6 Apr 2020

Cited by 20 | Viewed by 5677

Abstract

Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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14 pages, 1431 KiB

Open AccessReview

Hepatitis C Virus: Evading the Intracellular Innate Immunity

by Ana Rita Ferreira, Bruno Ramos, Alexandre Nunes and Daniela Ribeiro

J. Clin. Med. 2020, 9(3), 790; https://doi.org/10.3390/jcm9030790 - 13 Mar 2020

Cited by 19 | Viewed by 4747

Abstract

Hepatitis C virus (HCV) infections constitute a major public health problem and are the main cause of chronic hepatitis and liver disease worldwide. The existing drugs, while effective, are expensive and associated with undesirable secondary effects. There is, hence, an urgent need to develop novel therapeutics, as well as an effective vaccine to prevent HCV infection. Understanding the interplay between HCV and the host cells will certainly contribute to better comprehend disease progression and may unravel possible new cellular targets for the development of novel antiviral therapeutics. Here, we review and discuss the interplay between HCV and the host cell innate immunity. We focus on the different cellular pathways that respond to, and counteract, HCV infection and highlight the evasion strategies developed by the virus to escape this intracellular response. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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25 pages, 3895 KiB

Open AccessReview

Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections

by Sébastien Lhomme, Olivier Marion, Florence Abravanel, Jacques Izopet and Nassim Kamar

J. Clin. Med. 2020, 9(2), 331; https://doi.org/10.3390/jcm9020331 - 24 Jan 2020

Cited by 86 | Viewed by 8685

Abstract

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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16 pages, 1791 KiB

Open AccessReview

Targeting the Host for New Therapeutic Perspectives in Hepatitis D

by Vincent Turon-Lagot, Antonio Saviano, Catherine Schuster, Thomas F. Baumert and Eloi R. Verrier

J. Clin. Med. 2020, 9(1), 222; https://doi.org/10.3390/jcm9010222 - 14 Jan 2020

Cited by 16 | Viewed by 8465

Abstract

Hepatitis D virus (HDV) is a small satellite virus of hepatitis B virus (HBV) requiring HBV infection to complete its life cycle. It has been recently estimated that 13% of chronic HBV infected patients (60 million) are co-infected with HDV. Chronic hepatitis D is the most severe form of viral hepatitis with the highest risk to develop cirrhosis and liver cancer. Current treatment is based on pegylated-interferon-alpha which rarely controls HDV infection and is complicated by serious side effects. The development of novel antiviral strategies based on host targeting agents has shown promising results in phase I/II clinical trials. This review summarizes HDV molecular virology and physiopathology as well as new therapeutic approaches targeting HDV host factors. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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16 pages, 1281 KiB

Open AccessReview

Isolated Anti-HBc: Significance and Management

by Florian MORETTO, François-Xavier CATHERINE, Clémentine ESTEVE, Mathieu BLOT and Lionel PIROTH

J. Clin. Med. 2020, 9(1), 202; https://doi.org/10.3390/jcm9010202 - 11 Jan 2020

Cited by 26 | Viewed by 6719

Abstract

Hepatitis B virus (HBV) infection is prevalent worldwide and is associated with dramatic levels of morbidity and mortality. Isolated anti-HBc (IAHBc) is a particular serological pattern that is commonly found in immunocompromised patients. There is ongoing debate regarding the management of patients with IAHBc. Herein, we summarize the current guidelines and the newest evidence. The frequency of IAHBc is variable, with a higher prevalence in some populations, such as persons living with HIV and others immunocompromised patients. The risk of HBV reactivation depends on host factors (including immunosuppression) and viral factors. It is now well established that immunocompromised patients can be classified into three groups for risk according to the type of immunosuppression and/or treatment. In patients at high risk, HBV therapy has to be considered systematically. In patients at moderate risk, the decision is based on the level of HBV DNA (preemptive treatment or monitoring and vaccination). In patients with low risk, HBV vaccination is another possible approach, although further studies are needed to assess the type of preemptive strategy. Full article

(This article belongs to the Special Issue Immunobiology Pathogenesis and Therapeutic Perspectives in Viral Hepatitis)

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