Genes

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14 pages, 2971 KiB

Open AccessArticle

The Global Hepatitis B Virus Genotype Distribution Approximated from Available Genotyping Data

by Stoyan Velkov, Jördis J. Ott, Ulrike Protzer and Thomas Michler

Genes 2018, 9(10), 495; https://doi.org/10.3390/genes9100495 - 15 Oct 2018

Cited by 111 | Viewed by 12865

Abstract

Hepatitis B virus (HBV) is divided into nine genotypes, A to I. Currently, it remains unclear how the individual genotypes contribute to the estimated 250 million chronic HBV infections. We performed a literature search on HBV genotyping data throughout the world. Over 900 [...] Read more.

Hepatitis B virus (HBV) is divided into nine genotypes, A to I. Currently, it remains unclear how the individual genotypes contribute to the estimated 250 million chronic HBV infections. We performed a literature search on HBV genotyping data throughout the world. Over 900 publications were assessed and data were extracted from 213 records covering 125 countries. Using previously published HBV prevalence, and population data, we approximated the number of infections with each HBV genotype per country and the genotype distribution among global chronic HBV infections. We estimated that 96% of chronic HBV infections worldwide are caused by five of the nine genotypes: genotype C is most common (26%), followed by genotype D (22%), E (18%), A (17%) and B (14%). Genotypes F to I together cause less than 2% of global chronic HBV infections. Our work provides an up-to-date analysis of global HBV genotyping data and an initial approach to estimate how genotypes contribute to the global burden of chronic HBV infection. Results highlight the need to provide HBV cell culture and animal models that cover at least genotypes A to E and represent the vast majority of global HBV infections to test novel treatment strategies. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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20 pages, 911 KiB

Open AccessArticle

Molecular Characterization of Near Full-Length Genomes of Hepatitis B Virus Isolated from Predominantly HIV Infected Individuals in Botswana

by Motswedi Anderson, Wonderful Tatenda Choga, Sikhulile Moyo, Trevor Graham Bell, Tshepiso Mbangiwa, Bonolo Bonita Phinius, Lynnette Bhebhe, Theresa Kibirige Sebunya, Shahin Lockman, Richard Marlink, Anna Kramvis, Max Essex, Rosemary Mubanga Musonda, Jason Tory Blackard and Simani Gaseitsiwe

Genes 2018, 9(9), 453; https://doi.org/10.3390/genes9090453 - 7 Sep 2018

Cited by 13 | Viewed by 5401

Abstract

The World Health Organization plans to eliminate hepatitis B and C Infections by 2030. Therefore, there is a need to study and understand hepatitis B virus (HBV) epidemiology and viral evolution further, including evaluating occult (HBsAg-negative) HBV infection (OBI), given that such infections [...] Read more.

The World Health Organization plans to eliminate hepatitis B and C Infections by 2030. Therefore, there is a need to study and understand hepatitis B virus (HBV) epidemiology and viral evolution further, including evaluating occult (HBsAg-negative) HBV infection (OBI), given that such infections are frequently undiagnosed and rarely treated. We aimed to molecularly characterize HBV genomes from 108 individuals co-infected with human immunodeficiency virus (HIV) and chronic hepatitis B (CHB) or OBI identified from previous HIV studies conducted in Botswana from 2009 to 2012. Full-length (3.2 kb) and nearly full-length (~3 kb) genomes were amplified by nested polymerase chain reaction (PCR). Sequences from OBI participants were compared to sequences from CHB participants and GenBank references to identify OBI-unique mutations. HBV genomes from 50 (25 CHB and 25 OBI) individuals were successfully genotyped. Among OBI participants, subgenotype A1 was identified in 12 (48%), D3 in 12 (48%), and E in 1 (4%). A similar genotype distribution was observed in CHB participants. Whole HBV genome sequences from Botswana, representing OBI and CHB, were compared for the first time. There were 43 OBI-unique mutations, of which 26 were novel. Future studies using larger sample sizes and functional analysis of OBI-unique mutations are warranted. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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16 pages, 1300 KiB

Open AccessArticle

In Silico Analysis of Hepatitis B Virus Occult Associated Mutations in Botswana Using a Novel Algorithm

by Motswedi Anderson, Wonderful T. Choga, Sikhulile Moyo, Trevor Graham Bell, Tshepiso Mbangiwa, Bonolo B. Phinius, Lynette Bhebhe, Theresa K. Sebunya, Joseph Makhema, Richard Marlink, Anna Kramvis, Max Essex, Rosemary M. Musonda, Jason T. Blackard and Simani Gaseitsiwe

Genes 2018, 9(9), 420; https://doi.org/10.3390/genes9090420 - 21 Aug 2018

Cited by 8 | Viewed by 4742

Abstract

Occult hepatitis B infections (OBI) represent a reservoir of undiagnosed and untreated hepatitis B virus (HBV), hence the need to identify mutations that lead to this phenotype. Functionally characterizing these mutations by in vitro studies is time-consuming and expensive. To bridge this gap, [...] Read more.

Occult hepatitis B infections (OBI) represent a reservoir of undiagnosed and untreated hepatitis B virus (HBV), hence the need to identify mutations that lead to this phenotype. Functionally characterizing these mutations by in vitro studies is time-consuming and expensive. To bridge this gap, in silico approaches, which predict the effect of amino acid (aa) variants on HBV protein function, are necessary. We developed an algorithm for determining the relevance of OBI-associated mutations using in silico approaches. A 3 kb fragment of subgenotypes A1 and D3 from 24 chronic HBV-infected (CHB) and 24 OBI participants was analyzed. To develop and validate the algorithm, the effects of 68 previously characterized occult-associated mutations were determined using three computational tools: PolyPhen2, SNAP2, and PROVEAN. The percentage of deleterious mutations (with impact on protein function) predicted were 52 (76.5%) by PolyPhen2, 55 (80.9%) by SNAP2, and 65 (95.6%) by PROVEAN. At least two tools correctly predicted 59 (86.8%) mutations as deleterious. To identify OBI-associated mutations exclusive to Botswana, study sequences were compared to CHB sequences from GenBank. Of the 43 OBI-associated mutations identified, 26 (60.5%) were predicted by at least two tools to have an impact on protein function. To our knowledge, this is the first study to use in silico approaches to determine the impact of OBI-associated mutations, thereby identifying potential candidates for functional analysis to facilitate mechanistic studies of the OBI phenotype. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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14 pages, 1889 KiB

Open AccessArticle

Long-Term Follow-Up of Acute Hepatitis B: New Insights in Its Natural History and Implications for Antiviral Treatment

by Stefano Menzo, Claudia Minosse, Donatella Vincenti, Laura Vincenzi, Fabio Iacomi, Paola Zaccaro, Gianpiero D’Offizi and Maria R. Capobianchi

Genes 2018, 9(6), 293; https://doi.org/10.3390/genes9060293 - 12 Jun 2018

Cited by 9 | Viewed by 4199

Abstract

Acute hepatitis B infection (AHB) is still a common viral acute hepatitis worldwide. As vaccination, antiviral treatment, and immigration are bound to affect the epidemiological landscape of HBV infections, and some of its aspects need to be investigated: (1) the circulation of vaccine [...] Read more.

Acute hepatitis B infection (AHB) is still a common viral acute hepatitis worldwide. As vaccination, antiviral treatment, and immigration are bound to affect the epidemiological landscape of HBV infections, and some of its aspects need to be investigated: (1) the circulation of vaccine escape mutants and of primary drug resistant strains; (2) the change in HBV genotype prevalence; and (3) the clinical implications of AHB and the probability of chronification. The serological, virological, and clinical parameters of 75 patients, acutely infected by HBV, were gathered for a retrospective study. Long-term follow up, either to complete seroconversion or for up to five years, was possible for 44 patients. Sequence analysis of the reverse transcriptase/HBsAg and precore regions was performed to investigate the molecular epidemiology and pathogenesis of recent infections by HBV. Genotype distribution in AHB in Italian patients was radically different from that of chronic infections, with a dramatic increase of extra-European genotypes (A1, F), suggesting that a proportion of AHBs are currently related to imported strains. None of the documented infections occurred in vaccinated individuals, while HBsAg variants (potentially vaccine escape variants) were rare and less prevalent than in chronic infections. No drug resistant strains were observed. Spontaneous viral clearance occurred in all but three cases. Time to viral clearance was inversely proportional to liver damage, but HBsAg titer on day 28 and, better still, HBsAg decay from day 0 to day 28 after admission, were the best predictors of chronification. They are, thus, potentially useful to guide antiviral treatment to prevent chronic evolution. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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13 pages, 748 KiB

Open AccessArticle

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

by Tshepiso Mbangiwa, Ishmael Kasvosve, Motswedi Anderson, Prisca K. Thami, Wonderful T. Choga, Austen Needleman, Bonolo B. Phinius, Sikhulile Moyo, Melvin Leteane, Jean Leidner, Jason T. Blackard, Gloria Mayondi, Betsy Kammerer, Rosemary M. Musonda, Max Essex, Shahin Lockman and Simani Gaseitsiwe

Genes 2018, 9(5), 259; https://doi.org/10.3390/genes9050259 - 17 May 2018

Cited by 27 | Viewed by 6165

Abstract

The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women [...] Read more.

The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women in Botswana. Samples from 752 pregnant women were tested for hepatitis B surface antigen (HBsAg), and HBsAg-positive samples were tested for hepatitis B e antigen (HBeAg) and HBV DNA load. Samples that were HBsAg negative were screened for occult HBV infection by determining the HBV DNA load. HBV genotypes were determined based on a 415-base-pair fragment of the surface gene. Among the 752 women tested during pregnancy or early postpartum, 16 (2.1%) (95% confidence interval (CI): 2.0–2.2) were HBsAg-positive. The prevalence of chronic HBV infection was higher (3.1%) among HIV-infected (95% CI: 3.0–3.2) compared with HIV-uninfected women (1.1%) (95% CI: 1.07–1.1, p = 0.057). Among the 622 HBsAg-negative women, the prevalence of occult HBV infection was 6.6% (95% CI: 6.5–6.7). Three of thirteen HBsAg-positive participants were HBeAg-positive, and all were HIV-negative. Of the 11 maternal samples successfully genotyped, five (45.5%) were genotype D3, five (45.5%) were genotype A1, and one was genotype E (9%). Low and similar proportions of HIV-infected and -uninfected pregnant women in Botswana had occult or chronic HBV infection. We identified a subset of HIV-negative pregnant women who had high HBV DNA levels and were HBeAg-positive, and thus likely to transmit HBV to their infants. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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Review

Jump to: Research

24 pages, 840 KiB

Open AccessReview

The Role of Hepatitis B Core-Related Antigen

by Takako Inoue and Yasuhito Tanaka

Genes 2019, 10(5), 357; https://doi.org/10.3390/genes10050357 - 9 May 2019

Cited by 54 | Viewed by 7156

Abstract

Hepatitis B virus (HBV) cannot be completely eliminated from infected hepatocytes due to the existence of intrahepatic covalently closed circular DNA (cccDNA). Serological biomarkers reflect intrahepatic viral replicative activity as non-invasive alternatives to liver biopsy. Hepatitis B core-related antigen (HBcrAg) is a novel [...] Read more.

Hepatitis B virus (HBV) cannot be completely eliminated from infected hepatocytes due to the existence of intrahepatic covalently closed circular DNA (cccDNA). Serological biomarkers reflect intrahepatic viral replicative activity as non-invasive alternatives to liver biopsy. Hepatitis B core-related antigen (HBcrAg) is a novel biomarker that has an important role in chronic hepatitis B (CHB), because it correlates with serum HBV DNA and intrahepatic cccDNA. In clinical cases with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with promising outcomes for CHB patients. HBcrAg can predict spontaneous or treatment-induced hepatitis B envelope antigen (HBeAg) seroconversion, persistent responses before and after cessation of nucleos(t)ide analogues, potential HBV reactivation, HBV reinfection after liver transplantation, and risk of hepatocellular carcinoma progression or recurrence. In this review, the clinical applications of HBcrAg in CHB patients based on its virological features are described. Furthermore, new potential therapeutic anti-HBV agents that affect intrahepatic cccDNA are under development, and the monitoring of HBcrAg might be useful to judge therapeutic effects. In conclusion, HBcrAg might be a suitable surrogate marker beyond other HBV markers to predict the disease progression and treatment responses of CHB patients. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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8 pages, 485 KiB

Open AccessReview

Meeting the Challenge of Eliminating Chronic Hepatitis B Infection

by Peter A. Revill, Capucine Penicaud, Christian Brechot and Fabien Zoulim

Genes 2019, 10(4), 260; https://doi.org/10.3390/genes10040260 - 1 Apr 2019

Cited by 26 | Viewed by 5499

Abstract

Over 257 million people live with chronic hepatitis B virus (HBV) infection and there is no known cure. The effective preventative vaccine has no impact on existing infection. Despite the existence of drugs which efficiently suppress viral replication, treatment is usually life-long and [...] Read more.

Over 257 million people live with chronic hepatitis B virus (HBV) infection and there is no known cure. The effective preventative vaccine has no impact on existing infection. Despite the existence of drugs which efficiently suppress viral replication, treatment is usually life-long and finite therapies that cure HBV infection are urgently required. However, even if such therapies were available today, it is unlikely they would reach all of those who need it most, due to chronic hepatitis B (CHB) being largely undiagnosed across the globe and to the dire need for health systems promoting access to therapy. Considerable challenges to developing and implementing an effective HBV cure remain. Nonetheless, important advances towards a cure are being made, both in the development of a multitude of new therapeutic agents currently undergoing clinical trials, and through the establishment of a new global initiative dedicated to an HBV cure, ICE-HBV, that is working together with existing organisations to fast-track an HBV cure available to all. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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16 pages, 2177 KiB

Open AccessReview

Epidemiology of Hepatitis B Virus Infection in Bangladesh: Prevalence among General Population, Risk Groups and Genotype Distribution

by Md. Hassan Uz-Zaman, Ayesha Rahman and Mahmuda Yasmin

Genes 2018, 9(11), 541; https://doi.org/10.3390/genes9110541 - 8 Nov 2018

Cited by 20 | Viewed by 9310

Abstract

Despite a considerable body of published research on hepatitis B in Bangladesh, researchers continue to lament the lack of reliable information about hepatitis B virus (HBV) infection epidemiology. The present review aims to provide a comprehensive survey of the literature with particular focus [...] Read more.

Despite a considerable body of published research on hepatitis B in Bangladesh, researchers continue to lament the lack of reliable information about hepatitis B virus (HBV) infection epidemiology. The present review aims to provide a comprehensive survey of the literature with particular focus on a number of epidemiological questions, as well as a commentary on the trends of hepatitis B research as it has taken place in Bangladesh. The key themes to emerge from this review are: first, beyond noting a declining trend, it is difficult to provide conclusive estimates about HBV prevalence in the general population of Bangladesh. The majority of the studies, even the ones conducted on apparently healthy populations, fail to be adequately representative for the reasons explored in the article. Secondly, HBV infection in Bangladesh is sharply stratified across sociodemographic lines, which speaks to the role of awareness and risk exposure in HBV prevalence. Third, more research on occult infection rates is required to estimate the extent of risk posed by the current blood donation screening program, which relies exclusively on hepatitis B surface antigen as a biomarker. The same considerations apply for the comparative importance of vertical versus horizontal transmission and prevalence among particular risk groups like healthcare workers with high occupational exposure. Finally, while recent studies do allow us, albeit with some ambiguity, to draw conclusions about distribution of HBV genotypes in Bangladesh, there needs to be an added emphasis on molecular epidemiology. It is hoped that the present review, the first of its kind in Bangladesh, will serve as an up-to-date summary of the course HBV epidemiology research in Bangladesh has taken thus far, as well as crucial gaps to address going forward. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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24 pages, 919 KiB

Open AccessReview

Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure

by Anastasiya Kostyusheva, Dmitry Kostyushev, Sergey Brezgin, Elena Volchkova and Vladimir Chulanov

Genes 2018, 9(10), 483; https://doi.org/10.3390/genes9100483 - 5 Oct 2018

Cited by 12 | Viewed by 6653

Abstract

Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: [...] Read more.

Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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20 pages, 845 KiB

Open AccessReview

Viral Biomarkers in Chronic HBeAg Negative HBV Infection

by Emilia Hadziyannis and Andreas Laras

Genes 2018, 9(10), 469; https://doi.org/10.3390/genes9100469 - 27 Sep 2018

Cited by 50 | Viewed by 12188

Abstract

Viral biomarkers are important tools for monitoring chronic hepatitis B virus (HBV) hepatitis B early antigen (HBeAg) negative infection, both in its natural course as well as during and after treatment. The biomarkers consist of antibodies against viral epitopes, viral proteins, and molecular [...] Read more.

Viral biomarkers are important tools for monitoring chronic hepatitis B virus (HBV) hepatitis B early antigen (HBeAg) negative infection, both in its natural course as well as during and after treatment. The biomarkers consist of antibodies against viral epitopes, viral proteins, and molecular surrogate markers of the quantity and transcriptional activity of the stable episomal HBV covalently closed circular DNA (cccDNA) which is located in the nuclei of the infected hepatocytes. HBV deoxyribonucleic acid (DNA) or else viral load measurement in plasma or serum is a marker of HBV replication of major clinical importance. HBV DNA is used for staging and treatment monitoring as described in international scientific guidelines. Quantification of HBV antigens, mainly hepatitis B surface antigen (HBsAg) as well as Hepatitis B core related antigen (HBcrAg), play an important yet secondary role, especially in cases of low or undetectable HBV DNA and has been evaluated for the classification of the inactive carrier state, as a predictor of subsequent HBsAg clearance, treatment outcome, and development of hepatocellular carcinoma (HCC). The measurement of the replicative intermediate HBV RNA in serum is currently evaluated and may also prove to be a significant biomarker particularly in patients treated with nucleot(s)ide analogs. This review focuses on the viral biomarkers mentioned above and their role in HBV, HBeAg negative, infection. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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18 pages, 1811 KiB

Open AccessReview

Cellular Genomic Sites of Hepatitis B Virus DNA Integration

by Magdalena A. Budzinska, Nicholas A. Shackel, Stephan Urban and Thomas Tu

Genes 2018, 9(7), 365; https://doi.org/10.3390/genes9070365 - 20 Jul 2018

Cited by 56 | Viewed by 9543

Abstract

Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These [...] Read more.

Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These reported pathways include: induction of chromosomal instability; generation of insertional mutagenesis in key cancer-associated genes; transcription of downstream cancer-associated cellular genes; and/or formation of a persistent source of viral protein expression (particularly HBV surface and X proteins). The contribution of each of these specific mechanisms towards carcinogenesis is currently unclear. Here, we review the current knowledge of specific sites of HBV DNA integration into the host genome, which sheds light on these mechanisms. We give an overview of previously-used methods to detect HBV DNA integration and the enrichment of integration events in specific functional and structural cellular genomic sites. Finally, we posit a theoretical model of HBV DNA integration during disease progression and highlight open questions in the field. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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15 pages, 2665 KiB

Open AccessReview

Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

by Kristie Bloom, Mohube Betty Maepa, Abdullah Ely and Patrick Arbuthnot

Genes 2018, 9(4), 207; https://doi.org/10.3390/genes9040207 - 12 Apr 2018

Cited by 64 | Viewed by 10085

Abstract

Chronic infection with the hepatitis B virus (HBV) is a global health concern and accounts for approximately 1 million deaths annually. Amongst other limitations of current anti-HBV treatment, failure to eliminate the viral covalently closed circular DNA (cccDNA) and emergence of resistance remain [...] Read more.

Chronic infection with the hepatitis B virus (HBV) is a global health concern and accounts for approximately 1 million deaths annually. Amongst other limitations of current anti-HBV treatment, failure to eliminate the viral covalently closed circular DNA (cccDNA) and emergence of resistance remain the most worrisome. Viral rebound from latent episomal cccDNA reservoirs occurs following cessation of therapy, patient non-compliance, or the development of escape mutants. Simultaneous viral co-infections, such as by HIV-1, further complicate therapeutic interventions. These challenges have prompted development of novel targeted hepatitis B therapies. Given the ease with which highly specific and potent nucleic acid therapeutics can be rationally designed, gene therapy has generated interest for antiviral application. Gene therapy strategies developed for HBV include gene silencing by harnessing RNA interference, transcriptional inhibition through epigenetic modification of target DNA, genome editing by designer nucleases, and immune modulation with cytokines. DNA-binding domains and effectors based on the zinc finger (ZF), transcription activator-like effector (TALE), and clustered regularly interspaced short palindromic repeat (CRISPR) systems are remarkably well suited to targeting episomal cccDNA. This review discusses recent developments and challenges facing the field of anti-HBV gene therapy, its potential curative significance and the progress towards clinical application. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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15 pages, 2900 KiB

Open AccessReview

Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells

by Saravana Kumar Kailasam Mani and Ourania Andrisani

Genes 2018, 9(3), 137; https://doi.org/10.3390/genes9030137 - 2 Mar 2018

Cited by 40 | Viewed by 8810

Abstract

Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, [...] Read more.

Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs. Full article

(This article belongs to the Special Issue Hepatitis B Virus Infection: An Update on Epidemiology, Diagnosis, Treatment and Prevention)

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