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Editorial

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4 pages, 194 KiB

Open AccessEditorial

Special Issue “Hepatitis B Virus Infection: From Diagnostics to Treatments”

by Thomas Tu and Mark W. Douglas

Viruses 2020, 12(12), 1366; https://doi.org/10.3390/v12121366 - 30 Nov 2020

Cited by 13 | Viewed by 6502

Abstract

In this Special Issue, we have brought together a broad range of studies on hepatitis B virus (HBV) covering diagnosis, pathogenesis, monitoring, and treatment [...] Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

Research

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15 pages, 3820 KiB

Open AccessArticle

Global Occurrence of Clinically Relevant Hepatitis B Virus Variants as Found by Analysis of Publicly Available Sequencing Data

by Stoyan Velkov, Ulrike Protzer and Thomas Michler

Viruses 2020, 12(11), 1344; https://doi.org/10.3390/v12111344 - 23 Nov 2020

Cited by 12 | Viewed by 3190

Abstract

Several viral factors impact the natural course of hepatitis B virus (HBV) infection, the sensitivity of diagnostic tests, or treatment response to interferon-α and nucleos(t)ide analogues. These factors include the viral genotype and serotype but also mutations affecting the HBV surface antigen, basal [...] Read more.

Several viral factors impact the natural course of hepatitis B virus (HBV) infection, the sensitivity of diagnostic tests, or treatment response to interferon-α and nucleos(t)ide analogues. These factors include the viral genotype and serotype but also mutations affecting the HBV surface antigen, basal core promoter/pre-core region, or reverse transcriptase. However, a comprehensive overview of the distribution of HBV variants between HBV genotypes or different geographical locations is lacking. To address this, we performed an in silico analysis of publicly available HBV full-length genome sequences. We found that not only the serotype frequency but also the majority of clinically relevant mutations are primarily associated with specific genotypes. Distinct mutations enriched in certain world regions are not explained by the local genotype distribution. Two HBV variants previously identified to confer resistance to the nucleotide analogue tenofovir in vitro were not identified, questioning their translational relevance. In summary, our work elucidates the differences in the clinical manifestation of HBV infection observed between genotypes and geographical locations and furthermore helps identify suitable diagnostic tests and therapies. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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13 pages, 3988 KiB

Open AccessArticle

Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo

by Emma Morrish, Liana Mackiewicz, Natasha Silke, Marc Pellegrini, John Silke, Gabriela Brumatti and Gregor Ebert

Viruses 2020, 12(8), 901; https://doi.org/10.3390/v12080901 - 17 Aug 2020

Cited by 8 | Viewed by 4312

Abstract

Chronic hepatitis B virus (HBV) infection remains a global health threat and affects hundreds of millions worldwide. Small molecule compounds that mimic natural antagonists of inhibitor of apoptosis (IAP) proteins, known as Smac-mimetics (second mitochondria-derived activator of caspases-mimetics), can promote the death of [...] Read more.

Chronic hepatitis B virus (HBV) infection remains a global health threat and affects hundreds of millions worldwide. Small molecule compounds that mimic natural antagonists of inhibitor of apoptosis (IAP) proteins, known as Smac-mimetics (second mitochondria-derived activator of caspases-mimetics), can promote the death of HBV-replicating liver cells and promote clearance of infection in preclinical models of HBV infection. The Smac-mimetic birinapant is a substrate of the multidrug resistance protein 1 (MDR1) efflux pump, and therefore inhibitors of MDR1 increase intracellular concentration of birinapant in MDR1 expressing cells. Liver cells are known to express MDR1 and other drug pump proteins. In this study, we investigated whether combining the clinical drugs, birinapant and the MDR1 inhibitor zosuquidar, increases the efficacy of birinapant in killing HBV expressing liver cells. We showed that this combination treatment is well tolerated and, compared to birinapant single agent, was more efficient at inducing death of HBV-positive liver cells and improving HBV-DNA and HBV surface antigen (HBsAg) control kinetics in an immunocompetent mouse model of HBV infection. Thus, this study identifies a novel and safe combinatorial treatment strategy to potentiate substantial reduction of HBV replication using an IAP antagonist. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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15 pages, 2522 KiB

Open AccessArticle

Chronic Hepatitis B Infection Is Associated with Increased Molecular Degree of Inflammatory Perturbation in Peripheral Blood

by Caian L. Vinhaes, Luís A. B. Cruz, Rodrigo C. Menezes, Thomas A. Carmo, María B. Arriaga, Artur T. L. Queiroz, Manoel Barral-Netto and Bruno B. Andrade

Viruses 2020, 12(8), 864; https://doi.org/10.3390/v12080864 - 7 Aug 2020

Cited by 7 | Viewed by 3481

Abstract

Hepatitis B virus (HBV) infection remains a major public health concern. The interaction between HBV and the host inflammatory response is an important contributing factor driving liver damage and diseases outcomes. Here, we performed a retrospective analysis employing an adapted molecular degree of [...] Read more.

Hepatitis B virus (HBV) infection remains a major public health concern. The interaction between HBV and the host inflammatory response is an important contributing factor driving liver damage and diseases outcomes. Here, we performed a retrospective analysis employing an adapted molecular degree of perturbation (MDP) score system to assess the overall inflammatory imbalance related to persistent HBV infection. Plasma levels of several cytokines, chemokines, and other inflammatory markers were measured in Brazilian individuals diagnosed with either chronic HBV or previous HBV infection, as well as in uninfected controls between 2006 and 2007. Multidimensional analyses were used to depict and compare the overall expression profile of inflammatory markers between distinct clinical groups. Chronic HBV patients exhibited a marked inflammatory imbalance, characterized by heightened MDP scores and a distinct profile of correlation networks inputting plasma concentrations of the biomarkers, compared with either individuals with previous HBV or controls. Furthermore, in participants with chronic HBV infection, the viral loads in peripheral blood were directly proportional to overall molecular perturbation as well as to specific perturbations of interleukin (IL)-4 and interferon (IFN)-γ concentrations. These findings highlight additional nuances about systemic inflammation related to persistent HBV infection. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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31 pages, 3139 KiB

Open AccessArticle

In Silico Prediction of Human Leukocytes Antigen (HLA) Class II Binding Hepatitis B Virus (HBV) Peptides in Botswana

by Wonderful Tatenda Choga, Motswedi Anderson, Edward Zumbika, Bonolo B. Phinius, Tshepiso Mbangiwa, Lynnette N. Bhebhe, Kabo Baruti, Peter Opiyo Kimathi, Kaelo K. Seatla, Rosemary M. Musonda, Trevor Graham Bell, Sikhulile Moyo, Jason T. Blackard and Simani Gaseitsiwe

Viruses 2020, 12(7), 731; https://doi.org/10.3390/v12070731 - 6 Jul 2020

Cited by 9 | Viewed by 4998

Abstract

Hepatitis B virus (HBV) is the primary cause of liver-related malignancies worldwide, and there is no effective cure for chronic HBV infection (CHB) currently. Strong immunological responses induced by T cells are associated with HBV clearance during acute infection; however, the repertoire of [...] Read more.

Hepatitis B virus (HBV) is the primary cause of liver-related malignancies worldwide, and there is no effective cure for chronic HBV infection (CHB) currently. Strong immunological responses induced by T cells are associated with HBV clearance during acute infection; however, the repertoire of epitopes (epi) presented by major histocompatibility complexes (MHCs) to elicit these responses in various African populations is not well understood. In silico approaches were used to map and investigate 15-mers HBV peptides restricted to 9 HLA class II alleles with high population coverage in Botswana. Sequences from 44 HBV genotype A and 48 genotype D surface genes (PreS/S) from Botswana were used. Of the 1819 epi bindings predicted, 20.2% were strong binders (SB), and none of the putative epi bind to all the 9 alleles suggesting that multi-epitope, genotype-based, population-based vaccines will be more effective against HBV infections as opposed to previously proposed broad potency epitope-vaccines which were assumed to work for all alleles. In total, there were 297 unique epi predicted from the 3 proteins and amongst, S regions had the highest number of epi (n = 186). Epitope-densities (D_epi) between genotypes A and D were similar. A number of mutations that hindered HLA-peptide binding were observed. We also identified antigenic and genotype-specific peptides with characteristics that are well suited for the development of sensitive diagnostic kits. This study identified candidate peptides that can be used for developing multi-epitope vaccines and highly sensitive diagnostic kits against HBV infection in an African population. Our results suggest that viral variability may hinder HBV peptide-MHC binding, required to initiate a cascade of immunological responses against infection. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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13 pages, 1859 KiB

Open AccessArticle

Hepatitis B Virus-X Downregulates Expression of Selenium Binding Protein 1

by Young-Man Lee, Soojin Kim, Ran-Young Park and Yeon-Soo Kim

Viruses 2020, 12(5), 565; https://doi.org/10.3390/v12050565 - 20 May 2020

Cited by 8 | Viewed by 3794

Abstract

Selenium binding protein 1 (SELENBP1) has been known to be reduced in various types cancer, and epigenetic change is shown to be likely to account for the reduction of SELNEBP1 expression. With cDNA microarray comparative analysis, we found that SELENBP1 is markedly decreased [...] Read more.

Selenium binding protein 1 (SELENBP1) has been known to be reduced in various types cancer, and epigenetic change is shown to be likely to account for the reduction of SELNEBP1 expression. With cDNA microarray comparative analysis, we found that SELENBP1 is markedly decreased in hepatitis B virus-X (HBx)-expressing cells. To clarify the effect of HBx on SELENBP1 expression, we compared the expression levels of SELENBP1 mRNA and protein by semi-quantitative RT-PCR, Northern blot, and Western blot. As expected, SELENBP1 expression was shown to be reduced in cells expressing HBx, and reporter gene analysis showed that the SELENBP1 promoter is repressed by HBx. In addition, the stepwise deletion of 5′ flanking promoter sequences resulted in a gradual decrease in basal promoter activity and inhibition of SELENBP1 expression by HBx. Moreover, immunohistochemistry on tissue microarrays containing 60 pairs of human liver tissue showed decreased intensity of SELENBP1 in tumor tissues as compared with their matched non-tumor liver tissues. Taken together, our findings suggest that inhibition of SELENBP1 expression by HBx might act as one of the causes in the development of hepatocellular carcinoma caused by HBV infection. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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9 pages, 345 KiB

Open AccessArticle

Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study

by Catherine Freeland, Sierra Bodor, Udara Perera and Chari Cohen

Viruses 2020, 12(3), 305; https://doi.org/10.3390/v12030305 - 11 Mar 2020

Cited by 29 | Viewed by 9078

Abstract

Chronic hepatitis B infection (HBV) disproportionately affects African Immigrant (AI) communities in the U.S., with a reported infection rate of 15%. HBV screening rates within these communities are low. This study sought to better understand the socio-cultural determinants associated with low HBV screening [...] Read more.

Chronic hepatitis B infection (HBV) disproportionately affects African Immigrant (AI) communities in the U.S., with a reported infection rate of 15%. HBV screening rates within these communities are low. This study sought to better understand the socio-cultural determinants associated with low HBV screening among AI communities and identify potential strategies to help inform the development of effective HBV education and screening interventions. Seventeen in-depth interviews were conducted with community health experts working in AI communities throughout the U.S. Interviews explored the potential impact of culture, perception of health, awareness of HBV, religious practices, current screening practice, provider relationship, and behaviors towards general prevention. Interview data were analyzed using thematic analysis. Religious preferences and cultural norms affect health care access, perceptions towards prevention, awareness of HBV, and contribute to myths and stigma within this population. Participants reported a lack of HBV knowledge and awareness and barriers to health care access including, cost, language, racism, understanding of Western Medicine, and usage of traditional medicine. This study elucidates the role of religious and cultural beliefs as barriers to HBV screening and care. Results can contribute to public health efforts to increase awareness, screening and vaccination efforts within AI communities. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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Review

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25 pages, 3119 KiB

Open AccessReview

Animal Models of Hepatitis B Virus Infection–Success, Challenges, and Future Directions

by Yongzhen Liu, Stephanie Maya and Alexander Ploss

Viruses 2021, 13(5), 777; https://doi.org/10.3390/v13050777 - 28 Apr 2021

Cited by 36 | Viewed by 6628

Abstract

Chronic hepatitis B virus (HBV) infection affects more than 250 million people worldwide, which greatly increases the risk for terminal liver diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC). Even though current approved antiviral therapies, including pegylated type I interferon (IFN) and [...] Read more.

Chronic hepatitis B virus (HBV) infection affects more than 250 million people worldwide, which greatly increases the risk for terminal liver diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC). Even though current approved antiviral therapies, including pegylated type I interferon (IFN) and nucleos(t)ide analogs, can effectively suppress viremia, HBV infection is rarely cured. Since HBV exhibits a narrow species tropism and robustly infects only humans and higher primates, progress in HBV research and preclinical testing of antiviral drugs has been hampered by the scarcity of suitable animal models. Fortunately, a series of surrogate animal models have been developed for the study of HBV. An increased understanding of the barriers towards interspecies transmission has aided in the development of human chimeric mice and has greatly paved the way for HBV research in vivo, and for evaluating potential therapies of chronic hepatitis B. In this review, we summarize the currently available animal models for research of HBV and HBV-related hepadnaviruses, and we discuss challenges and future directions for improvement. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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11 pages, 730 KiB

Open AccessReview

HBV Prevention and Treatment in Countries of Central Asia and the Caucasus

by Daulet Amerzhanov, Indira Suleimenova, Salima Davlidova, Zhamilya Nugmanova and Syed Ali

Viruses 2020, 12(10), 1112; https://doi.org/10.3390/v12101112 - 30 Sep 2020

Cited by 9 | Viewed by 3056

Abstract

The countries of Central Asia and the Caucasus are linked by travel and trade, which is promoted by visa-free mobility across borders. Unfortunately, this migrant mobility has given rise to the transmission of various infections within this region. Overlaps in culture, tradition, and [...] Read more.

The countries of Central Asia and the Caucasus are linked by travel and trade, which is promoted by visa-free mobility across borders. Unfortunately, this migrant mobility has given rise to the transmission of various infections within this region. Overlaps in culture, tradition, and behavior among these countries provide opportunities to share experiences that have proven effective in controlling transmission. Here we present a review of hepatitis B virus (HBV) prevalence, prevention and treatment across Central Asia and the Caucasus. Overall, owing to effective measures, while HBV prevalence has been steadily declining in the region, certain gaps still exist regarding the generation and availability of HBV infection data. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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32 pages, 4074 KiB

Open AccessReview

Advanced Therapeutics, Vaccinations, and Precision Medicine in the Treatment and Management of Chronic Hepatitis B Viral Infections; Where Are We and Where Are We Going?

by Ganesh Selvaraj Duraisamy, Dattatry Bhosale, Ivana Lipenská, Ivana Huvarova, Daniel Růžek, Marc P. Windisch and Andrew D. Miller

Viruses 2020, 12(9), 998; https://doi.org/10.3390/v12090998 - 7 Sep 2020

Cited by 17 | Viewed by 5420

Abstract

The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha [...] Read more.

The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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16 pages, 626 KiB

Open AccessReview

The Yin and the Yang of Treatment for Chronic Hepatitis B—When to Start, When to Stop Nucleos(t)ide Analogue Therapy

by Samuel Hall, Jessica Howell, Kumar Visvanathan and Alexander Thompson

Viruses 2020, 12(9), 934; https://doi.org/10.3390/v12090934 - 25 Aug 2020

Cited by 12 | Viewed by 3571

Abstract

Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to [...] Read more.

Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed “treat-all” strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of “stopping” NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the “treat-all” strategy, as well as the “stop” strategy, and how they may both have a role in the management of patients with chronic hepatitis B. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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10 pages, 271 KiB

Open AccessReview

Innovative HBV Animal Models Based on the Entry Receptor NTCP

by Jochen M. Wettengel and Benjamin J. Burwitz

Viruses 2020, 12(8), 828; https://doi.org/10.3390/v12080828 - 30 Jul 2020

Cited by 16 | Viewed by 4183

Abstract

Hepatitis B is a major global health problem, with an estimated 257 million chronically infected patients and almost 1 million deaths per year. The causative agent is hepatitis B virus (HBV), a small, enveloped, partially double-stranded DNA virus. HBV has a strict species [...] Read more.

Hepatitis B is a major global health problem, with an estimated 257 million chronically infected patients and almost 1 million deaths per year. The causative agent is hepatitis B virus (HBV), a small, enveloped, partially double-stranded DNA virus. HBV has a strict species specificity, naturally infecting only humans and chimpanzees. Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter expressed on hepatocytes, has been shown to be one of the key factors in HBV infection, playing a crucial role in the HBV entry process in vitro and in vivo. Variations in the amino acid sequence of NTCP can inhibit HBV infection and, therefore, contributes, in part, to the species barrier. This discovery has revolutionized the search for novel animal models of HBV. Indeed, it was recently shown that variations in the amino acid sequence of NTCP represent the sole species barrier for HBV infection in macaques. Here, we review what is known about HBV entry through the NTCP receptor and highlight how this knowledge has been harnessed to build new animal models for the study of HBV pathogenesis and curative therapies. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

11 pages, 949 KiB

Open AccessReview

Elimination of Hepatitis B in Highly Endemic Settings: Lessons Learned in Taiwan and Challenges Ahead

by Chun-Jen Liu and Pei-Jer Chen

Viruses 2020, 12(8), 815; https://doi.org/10.3390/v12080815 - 28 Jul 2020

Cited by 32 | Viewed by 4123

Abstract

Hepatitis B virus (HBV) infection and its related liver diseases are important health problems worldwide, particularly in the Asia-Pacific region. For the past 4–5 decades, Taiwan’s government and scientists have cooperated together to control this virus infection and its related liver diseases. These [...] Read more.

Hepatitis B virus (HBV) infection and its related liver diseases are important health problems worldwide, particularly in the Asia-Pacific region. For the past 4–5 decades, Taiwan’s government and scientists have cooperated together to control this virus infection and its related liver diseases. These efforts and achievements have made progress toward the elimination of HBV. Taiwan’s government initiated the Viral Hepatitis Control Program (VHCP) in the1970s, and then launched the national vaccination program in 1984. This universal vaccination program effectively decreased the rate of hepatitis B carriage and the development of hepatocellular carcinoma (HCC) in the younger generation. Since 2003, approved anti-HBV treatments were reimbursed nationwide. This reimbursement program resulted in a higher uptake of anti-HBV treatments, which contributed to a decrease in liver-related disease progression and subsequently reduced attributable mortality in Taiwan. This experience can be shared by countries in other parts of the world regarding the control of chronic viral hepatitis B. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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19 pages, 2433 KiB

Open AccessReview

Molecular, Evolutionary, and Structural Analysis of the Terminal Protein Domain of Hepatitis B Virus Polymerase, a Potential Drug Target

by Timothy S. Buhlig, Anastasia F. Bowersox, Daniel L. Braun, Desiree N. Owsley, Kortney D. James, Alfredo J. Aranda, Connor D. Kendrick, Nicole A. Skalka and Daniel N. Clark

Viruses 2020, 12(5), 570; https://doi.org/10.3390/v12050570 - 22 May 2020

Cited by 10 | Viewed by 6913

Abstract

Approximately 250 million people are living with chronic hepatitis B virus (HBV) infections, which claim nearly a million lives annually. The target of all current HBV drug therapies (except interferon) is the viral polymerase; specifically, the reverse transcriptase domain. Although no high-resolution structure [...] Read more.

Approximately 250 million people are living with chronic hepatitis B virus (HBV) infections, which claim nearly a million lives annually. The target of all current HBV drug therapies (except interferon) is the viral polymerase; specifically, the reverse transcriptase domain. Although no high-resolution structure exists for the HBV polymerase, several recent advances have helped to map its functions to specific domains. The terminal protein (TP) domain, unique to hepadnaviruses such as HBV, has been implicated in the binding and packaging of the viral RNA, as well as the initial priming of and downstream synthesis of viral DNA—all of which make the TP domain an attractive novel drug target. This review encompasses three types of analysis: sequence conservation analysis, secondary structure prediction, and the results from mutational studies. It is concluded that the TP domain of HBV polymerase is comprised of seven subdomains (three unstructured loops and four helical regions) and that all three loop subdomains and Helix 5 are the major determinants of HBV function within the TP domain. Further studies, such as modeling inhibitors of these critical TP subdomains, will advance the TP domain of HBV polymerase as a therapeutic drug target in the progression towards a cure. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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20 pages, 500 KiB

Open AccessReview

The Lived Experience of Chronic Hepatitis B: A Broader View of Its Impacts and Why We Need a Cure

by Thomas Tu, Joan M. Block, Su Wang, Chari Cohen and Mark W. Douglas

Viruses 2020, 12(5), 515; https://doi.org/10.3390/v12050515 - 7 May 2020

Cited by 63 | Viewed by 10592

Abstract

Chronic hepatitis B (CHB) is one of the most widespread liver diseases in the world. It is currently incurable and can lead to liver cirrhosis and cancer. The considerable impacts on society caused by CHB through patient mortality, morbidity, and economic loss are [...] Read more.

Chronic hepatitis B (CHB) is one of the most widespread liver diseases in the world. It is currently incurable and can lead to liver cirrhosis and cancer. The considerable impacts on society caused by CHB through patient mortality, morbidity, and economic loss are well-recognised in the field. This is, however, a narrow view of the harms, given that people living with CHB can be asymptomatic for the majority of their life-long infection. Of less-appreciated importance are the psychosocial harms, which can continue throughout an affected person’s lifetime. Here we review the broad range of these impacts, which include fear and anxiety; financial loss and instability; stigma and discrimination; and rejection by society. Importantly, these directly affect patient diagnosis, management, and treatment. Further, we highlight the roles that the research community can play in taking these factors into account and mitigating them. In particular, the development of a cure for hepatitis B virus infection would alleviate many of the psychosocial impacts of CHB. We conclude that there should be a greater recognition of the full impacts associated with CHB to bring meaningful, effective, and deliverable results to the global community living with hepatitis B. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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23 pages, 1137 KiB

Open AccessReview

In Vitro Systems for Studying Different Genotypes/Sub-Genotypes of Hepatitis B Virus: Strengths and Limitations

by Constance N. Wose Kinge, Nimisha H. Bhoola and Anna Kramvis

Viruses 2020, 12(3), 353; https://doi.org/10.3390/v12030353 - 23 Mar 2020

Cited by 15 | Viewed by 6405

Abstract

Hepatitis B virus (HBV) infects the liver resulting in end stage liver disease, cirrhosis, and hepatocellular carcinoma. Despite an effective vaccine, HBV poses a serious health problem globally, accounting for 257 million chronic carriers. Unique features of HBV, including its narrow virus–host range [...] Read more.

Hepatitis B virus (HBV) infects the liver resulting in end stage liver disease, cirrhosis, and hepatocellular carcinoma. Despite an effective vaccine, HBV poses a serious health problem globally, accounting for 257 million chronic carriers. Unique features of HBV, including its narrow virus–host range and its hepatocyte tropism, have led to major challenges in the development of suitable in vivo and in vitro model systems to recapitulate the HBV replication cycle and to test various antiviral strategies. Moreover, HBV is classified into at least nine genotypes and 35 sub-genotypes with distinct geographical distributions and prevalence, which have different natural histories of infection, clinical manifestation, and response to current antiviral agents. Here, we review various in vitro systems used to study the molecular biology of the different (sub)genotypes of HBV and their response to antiviral agents, and we discuss their strengths and limitations. Despite the advances made, no system is ideal for pan-genotypic HBV research or drug development and therefore further improvement is required. It is necessary to establish a centralized repository of HBV-related generated materials, which are readily accessible to HBV researchers, with international collaboration toward advancement and development of in vitro model systems for testing new HBV antivirals to ensure their pan-genotypic and/or customized activity. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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14 pages, 1421 KiB

Open AccessReview

Impact of the Interaction of Hepatitis B Virus with Mitochondria and Associated Proteins

by Md. Golzar Hossain, Sharmin Akter, Eriko Ohsaki and Keiji Ueda

Viruses 2020, 12(2), 175; https://doi.org/10.3390/v12020175 - 4 Feb 2020

Cited by 28 | Viewed by 5595

Abstract

Around 350 million people are living with hepatitis B virus (HBV), which can lead to death due to liver cirrhosis and hepatocellular carcinoma (HCC). Various antiviral drugs/nucleot(s)ide analogues are currently used to reduce or arrest the replication of this virus. However, many studies [...] Read more.

Around 350 million people are living with hepatitis B virus (HBV), which can lead to death due to liver cirrhosis and hepatocellular carcinoma (HCC). Various antiviral drugs/nucleot(s)ide analogues are currently used to reduce or arrest the replication of this virus. However, many studies have reported that nucleot(s)ide analogue-resistant HBV is circulating. Cellular signaling pathways could be one of the targets against the viral replication. Several studies reported that viral proteins interacted with mitochondrial proteins and localized in the mitochondria, the powerhouse of the cell. And a recent study showed that mitochondrial turnover induced by thyroid hormones protected hepatocytes from hepatocarcinogenesis mediated by HBV. Strong downregulation of numerous cellular signaling pathways has also been reported to be accompanied by profound mitochondrial alteration, as confirmed by transcriptome profiling of HBV-specific CD8 T cells from chronic and acute HBV patients. In this review, we summarize the ongoing research into mitochondrial proteins and/or signaling involved with HBV proteins, which will continue to provide insight into the relationship between mitochondria and HBV and ultimately lead to advances in viral pathobiology and mitochondria-targeted antiviral therapy. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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29 pages, 1558 KiB

Open AccessReview

Host Transcription Factors in Hepatitis B Virus RNA Synthesis

by Kristi L. Turton, Vanessa Meier-Stephenson, Maulik D. Badmalia, Carla S. Coffin and Trushar R. Patel

Viruses 2020, 12(2), 160; https://doi.org/10.3390/v12020160 - 30 Jan 2020

Cited by 55 | Viewed by 8304

Abstract

The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA [...] Read more.

The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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Other

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11 pages, 1891 KiB

Open AccessBrief Report

A Simple and Cost-Effective DNA Preparation Method Suitable for High-Throughput PCR Quantification of Hepatitis B Virus Genomes

by Eunji Jo, Jaewon Yang, Alexander Koenig, Seung Kew Yoon and Marc P. Windisch

Viruses 2020, 12(9), 928; https://doi.org/10.3390/v12090928 - 24 Aug 2020

Cited by 2 | Viewed by 3904

Abstract

Hepatitis B virus (HBV) is a para-retrovirus that reverse transcribes its pregenomic RNA into relaxed circular DNA inside viral nucleocapsids. The number of HBV genomes produced in vitro is typically quantified using commercial silica-membrane-based nucleic acid purification kits to isolate total DNA followed [...] Read more.

Hepatitis B virus (HBV) is a para-retrovirus that reverse transcribes its pregenomic RNA into relaxed circular DNA inside viral nucleocapsids. The number of HBV genomes produced in vitro is typically quantified using commercial silica-membrane-based nucleic acid purification kits to isolate total DNA followed by HBV-specific quantitative PCR (qPCR). However, despite the convenience of commercial kits, this procedure is costly and time-consuming due to multiple centrifugation steps, which produce unnecessary waste. Here, we report a rapid, cost-effective, and environmentally friendly total DNA preparation method. The assay is based on the simple incubation of detergent and proteinase K with cells or cell-free supernatants to permeabilize cells and disrupt viral particles. After heat inactivation and subsequent centrifugation to clear the lysates, DNA samples are directly subjected to qPCR to quantify HBV genomes. As a proof of concept, the assay was developed in 12-well plates to assess intra- and extracellular HBV genome equivalents (GEqs) of stably viral-replicating cell lines (e.g., HepAD38) and HBV-infected HepG2-NTCP cells, both treated with lamivudine (LMV), an HBV replication inhibitor. Viral DNA was also prepared from the serum of patients chronically infected with HBV. To validate the assay, a representative commercial DNA isolation kit was used side-by-side to isolate intra- and extracellular HBV DNA. Both methods yielded comparable amounts of HBV GEqs with comparable LMV 50% efficient concentration (EC₅₀) values. The assay was subsequently adapted to 96- and 384-well microtiter plates using HepAD38 cells. The EC₅₀ values were comparable to those obtained in 12-well plates. In addition, the calculated coefficient of variation, Z’ values, and assay window demonstrated high reproducibility and quality. We devised a novel, robust, reproducible, high-throughput microtiter plate DNA preparation method suitable for quantifying HBV GEqs by qPCR analysis. This strategy enables rapid and convenient quantitative analysis of multiple viral DNA samples in parallel to investigate intracellular HBV replication and the secretion of DNA-containing viral particles. Full article

(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)

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