Article:Hepatitis B virus infection: Defective surface antigen expression and pathogenesis (6102499)

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Title: World Journal of Gastroenterology

Hepatitis B virus infection: Defective surface antigen expression and pathogenesis

  • Chun-Chen Wu
  • State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
  • Ying-Shan Chen
  • State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
  • Liang Cao
  • State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, ChinaDepartment of Microbiology and Immunology, Feinberg School of Medicine Northwestern University, Chicago, IL 60611, United States
  • Xin-Wen Chen
  • State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, Hubei Province, China
  • Meng-Ji Lu
  • Institute of Virology, University Hospital of Essen, Essen 45122, Germany.

Publication date (ppub): 8/2018

Publication date (epub): 8/2018


Hepatitis B virus (HBV) infection is a global public health concern. HBV causes chronic infection in patients and can lead to liver cirrhosis, hepatocellular carcinoma, and other severe liver diseases. Thus, understanding HBV-related pathogenesis is of particular importance for prevention and clinical intervention. HBV surface antigens are indispensable for HBV virion formation and are useful viral markers for diagnosis and clinical assessment. During chronic HBV infection, HBV genomes may acquire and accumulate mutations and deletions, leading to the expression of defective HBV surface antigens. These defective HBV surface antigens have been found to play important roles in the progression of HBV-associated liver diseases. In this review, we focus our discussion on the nature of defective HBV surface antigen mutations and their contribution to the pathogenesis of fulminant hepatitis B. The relationship between defective surface antigens and occult HBV infection are also discussed.


Core tip: Defective surface antigen mutation is a type of mutation with great clinical relevance. Many previous publications have explored the association of defective surface antigen mutation with the development of hepatitis B virus (HBV)-associated hepatocellular carcinoma. However, there are no reviews available that elaborate on the relationship between defective surface antigen mutation and HBV-associated fulminant hepatitis (FH), as well as occult hepatitis B virus infection (OBI). This review will focus on these two aspects to discuss the nature of defective HBV surface antigen mutations and their contribution to the pathogenesis of FH. The relationship between defective surface antigens and OBI are also discussed.


Hepatitis B virus (HBV) is an important human pathogen that has caused chronic infections worldwide[[1]]. Recent data obtained from a modeling study has shown that the global prevalence of hepatitis B surface antigen (HBsAg) was 3.9% in 2016, corresponding to an estimated 290 million infections worldwide[[2]]. HBV mainly infects hepatocytes and causes a wide spectrum of clinical manifestations, ranging from an asymptomatic carrier state to acute or chronic hepatitis, with progression to liver cirrhosis, hepatocellular carcinoma (HCC), and other severe liver diseases[[3],[4]]. Currently, interferon-α and nucleotide analogs are used to treat chronic HBV (CHB) infections; however, the outcome is far from satisfactory[[5],[6]]. Prophylaxis using the current HBV vaccines has no impact on existing infections. Therapeutic vaccines of chronic HBV infection are under investigation, but further development is still required[[7]]. Therefore, understanding the molecular pathogenesis of HBV infection will provide opportunities for the development of better therapies and vaccines.

HBV belongs to the family Hepadnaviridae and is a small, enveloped virus with a partially double-stranded DNA genome approximately 3.2 kb in size[[8]]. During the life cycle of HBV, pre-genomic RNA (pgRNA) is transcribed from covalently closed circular DNA (cccDNA) and serves as the template for HBV DNA replication through a viral polymerase-mediated reverse transcription[[9],[10]]. Because viral polymerase lacks a proof-reading function, the HBV genome evolves with an estimated rate of nucleotide substitutions of 1 × 10-3 to 1 × 10-6 per replication cycle, according to various investigators[[11]]. Although HBV genome replication involves a step of reverse transcription, which is similar to retroviral replication, the complex HBV genome structure with overlapping open reading frames and regulatory sequences apparently limits the spectrum and rate of mutations[[3],[12]]. Nevertheless, this unique replication strategy leads to the great diversity of HBV genomes, thus resulting in the occurrence of various genotypes, subtypes, mutants, recombinants, and even viral quasi-species in the context of long-term HBV evolution[[13],[14]]. Several reports have suggested that the emergence of HBV variants plays important roles in the progression of HBV-associated liver diseases[[11],[15]-[18]]. Defective surface antigen mutation is a type of mutation with great clinical relevance[[11],[15],[19]]. In this review, we report the current information on HBV surface antigen mutations. Further, we focus our discussion on the contribution of defective surface antigen mutations on the pathogenesis of HBV-associated liver diseases.


Three viral envelope/surface proteins - large surface antigens (LHBs), middle surface antigens (MHBs), and small surface antigens (SHBs) - are expressed from a single open reading frame (S-ORF)[[20],[21]], but they are translated from two different mRNAs. LHBs are encoded by the 2.4 kb subgenomic RNA, and MHBs and SHBs are encoded by the 2.1 kb subgenomic RNA[[3]]. Subgenomic RNAs of 2.4 kb and 2.1 kb are driven by preS1 and preS2/S promoters, respectively, allowing variable regulation of protein expression[[3]]. The preS1 promoter is situated within the upstream region of the S-ORF, whereas the preS2 promoter corresponds to the preS1 domain[[21]]. Therefore, the transcription of the 2.1 kb subgenomic RNA is also regulated by the preS1 domain[[11]] (Figure 1).

Figure 1

The transcription and expression of hepatitis B virus surface proteins. The three HBV surface proteins, LHBs, MHBs, and SHBs, are translated from two different mRNAs: LHBs are encoded by the preS1 promoter-initiated 2.4 kb subgenomic RNA; MHBs and SHBs are encoded by the preS2 promoter-initiated 2.1 kb subgenomic RNA. The 2.4 and 2.1 kb subgenomic RNAs share the same 3’ end and only differ in length due to differences at the 5’ end, which lead to different amino-terminal but identical carboxy-terminal regions of the three surface antigens. Therefore, LHBs contain preS1 + preS2 + S (389 or 400 aa residues), MHBs contain preS2 + S (281 aa residues), and SHBs contain the S domain (226 aa residues) alone. For mature/infectious virions, LHBs, MHBs, and SHBs are present in the envelopes at a ratio of approximately 1:1:4. In addition, the major fraction of SHBs forms subviral particles (filaments and spheres) together with the minor parts of LHBs and/or MHBs. HBV: Hepatitis B virus; LHBs: Large surface antigens; MHBs: Middle surface antigens; SHBs: Small surface antigens.

The three surface proteins share the same carboxy-terminal region and only differ in length due to their amino-terminal regions. As a result, the LHBs contain the preS1 + preS2 + S [389 or 400 amino acid (aa) residues], MHBs contain the preS2 + S (281 aa residues), and SHBs contain the S domain (226 aa residues) alone[[3],[20],[22]] (Figure 1). Additionally, a truncated and mutated preS2/S (the LHBs and truncated MHBs) can be produced by integrated viral sequences that are defective for replication[[23],[24]]. LHBs, MHBs, and SHBs are important for HBV structure and life cycle. Besides mediating HBV entry through binding to HBV receptors, the sodium taurocholate co-transporting polypeptide (NTCP) on hepatocytes, via the preS1 2-48 aa domain (numbering for HBV-genotype D) and subsequent infection, LHBs are indispensable for the formation and budding of virions[[3],[25]-[29]]. It has been proposed that LHBs rearrange their structure during the maturation of HBV virions and thereby regulate the release and infectivity of virions[[30]-[32]]. The exact role of MHBs in the HBV life cycle remains an enigma. Early reports indicated that MHBs might be dispensable for HBV replication and virion formation; however, our data and those of other groups have shown that MHBs play a role in virion secretion[[33]-[36]]. Recently, MHBs were found to interact with ceruloplasmin and influence the production of extracellular virions[[34]]. As the predominant component of viral particles, including infectious virions and noninfectious subviral particles, SHBs are necessary for the production of virions and subviral particles[[35]]. For mature/infectious virions, LHBs, MHBs, and SHBs are present in the envelopes at a ratio of approximately 1:1:4[[20]]. Disturbance of this proportion impairs the production and release of virions[[33]]. For subviral particles, their amount outnumbers virions by 10000- to 1000000-fold, and the particles are detected serologically as HBsAg[[11],[37]]. The secretion of subviral particles can also be suppressed by LHBs in a dose-dependent manner[[38]-[41]], thus promoting the S protein toward virion formation.

In addition, preS1, preS2, and S domains contain various B- and T-cell epitopes, which play an important role in inducing the host immune response[[42],[43]]. The major hydrophilic region (MHR) between aa 100-169 of SHBs, especially the a-determinant located at aa 124-147, serves as the most important antigenic determinant in HBV surface proteins and is essential for HBsAg detection and HBV vaccine development[[44],[45]]. Plasma-derived and recombinant HBsAg have been used for vaccine preparations and have induced strong specific and protective antibody responses in vaccines[[46]-[48]]. The presence of anti-HBs antibodies is considered to confer immunity against HBV infection. In contrast, a high quantity of circulating HBsAg in chronically HBV-infected patients is proposed as a factor leading to immune disturbance. Defective peripheral HBsAg-specific T cell responses in chronically infected patients were found to be correlated with serum HBsAg titers[[49],[50]], suggesting that HBsAg overproduction influences the host’s immune system in a way that is advantageous for the virus. In vitro, HBsAg can interfere with Toll-like receptor functions and trigger interleukin (IL)-10 production in Kuppfer cells[[51]-[54]]. Recently, published data has suggested that HBsAg may facilitate the induction of myeloid-derived suppressor cells in chronically HBV-infected patients[[55]]. HBsAg is also associated with the induction of regulatory T cells, as shown in HBV mouse models[[56],[57]]. Thus, HBsAg is not only a structural component of virions and subviral particles, but it also serves as an important immune modulator.


HBsAg mutants were first identified in individuals vaccinated against HBV but who were infected despite the presence of protective anti-HBs antibodies[[58]]. Those “immune escape” mutants with aa substitutions within a-determinants were found in different clinical settings, including vaccines, transplant patients receiving hyperimmunoglobulins, and immunocompromised patients with HBV reactivation[[59]-[61]]. Such mutant HBsAg commonly showed reduced binding to anti-HBs antibodies and decreased reactivity in established HBsAg detection assays[[59]-[65]]. The most widely known mutation is the sG145R mutation, which has been shown to be replication competent, may persist stably over time, and may be transmitted vertically or horizontally[[66]-[69]]. The sG145R mutation induces a strongly impaired anti-HBs antibody response, which could not efficiently clear HBsAg in an HBV hydrodynamic injection mouse model[[70]]. A similar result was also observed for another immune escape mutation, sK122I, indicating that such a defective surface antigen mutation may impair HBsAg neutralization and clearance during HBV infection. In addition, sG145R, sK122I, and other immune escape mutants occurring in the a-determinant of SHBs, such as the sT123N mutation, could affect HBsAg secretion[[70]-[73]].

Recently, chronically HBV-infected patients routinely received antiviral therapy based on nucleotide analogs[[74]]. Treatment with first-generation drugs, such as famciclovir and adeforvir, resulted in the emergence of drug-resistant HBV mutants, with aa substitutions within the HBV polymerase domain[[75]]. Some drug-resistant mutations occurring in the viral polymerase may lead to a stop codon mutation in the overlapping surface gene, cause intracellular retention of surface proteins, and result in secretion defects of viral particles, such as rtA181T/sW172*, rtM204I/sW196*, and rtV191I/sW182*, as shown in previous reports[[76]-[78]] and in our unpublished data. The primary sW182* mutation has also been identified in CHB patients. It was found to induce retention of the truncated S protein in the perinuclear endoplasmic reticulum (ER) and was associated with lower HBV transcript levels owing to decreased stability, but without impact on HBV replication[[79]].

Defective surface antigen mutations have been frequently detected in chronic HBV infection[[16],[71]-[73],[80],[81]], in which deletions in the preS domains are the most common mutations[[80],[81]]. Deletions in the preS domains are often clustered at the 3’ end of preS1 and the 5’ end of preS2[[11],[19],[81]-[83]]. Given that the preS2/S promoter is situated within the preS1 domain[[11]], deletions at the 3’ end of the preS1 may reduce MHBs and SHBs expression at the transcriptional level. Deletions at the 5’ end of the preS2 may remove the N-terminal preS2 domain, including the start codon of preS2 in the MHBs protein, leading to an impaired or complete loss of MHBs expression[[84]]. These changes may disrupt the proper LHBs, MHBs, and SHBs ratio in the envelopes of virions. In addition, the junction between the preS1 and preS2 domain is required for virion formation[[32]]. For these reasons, preS deletions may potentially affect virion assembly, stability, or infectivity.

A large amount of evidence has demonstrated that DHBV envelope proteins can regulate cccDNA formation and amplification[[85],[86]]. Infection of envelope protein-deficient recombinant DHBV results in more cccDNA accumulation[[85],[87],[88]]. Similarly, deficiencies in HBV envelope proteins can modestly increase the cccDNA level and result in a dramatic accumulation of deproteinized rcDNA[[89]-[91]]. It has been demonstrated that preS/S mutants with surface antigen secretion deficiency isolated from patients can lead to an increased accumulation of cccDNA molecules in the nuclei[[79]]. Therefore, defective surface antigen mutation may affect cccDNA synthesis and amplification.


Defective surface antigen mutations have been found in acute hepatitis B infection, chronic hepatitis B infection, and occult HBV infection and are associated with advanced liver disease, including liver cirrhosis, fulminant hepatitis B, and HCC[[15],[82],[92]-[105]]. It has been questioned whether HBV mutants arise due to viral adaptation to inflammation and decreased liver function or, alternatively, causally contribute to liver pathogenesis. The mechanism of defective surface antigen mutations to HCC development has been widely elucidated[[11],[23],[41],[106]-[111]]. Here, we will emphasize in our discussion the relationship between defective surface antigen mutations and fulminant hepatitis B, as well as occult HBV infection.

Defective surface antigen expression and fulminant hepatitis

There is increasing evidence that defective surface antigen expression may play a role in the pathogenesis of fulminant hepatitis (FH). preS deletions, particularly those unable to synthesize the MHBs protein, have been associated with cases of FH[[16],[71],[112],[113]], suggesting the potential pathogenic role of preS deletions. A mutation in the CAAT element of the S promoter has been found in the HBV genome isolated from an FH patient. This mutation led to excessive LHBs expression over MHBs and SHBs proteins and resulted in virus retention and misassembly[[114]-[116]]. Obviously, the accumulation of LHBs may be due to hepatocyte injury, as shown in transgenic mice with LHBs expression[[41]]. One of our previous studies also identified deletions within the preS regions from HBV strains isolated from a patient with HBV-associated FH[[84]]. In addition, a hepatitis B immune globulin (HBIG)-escape mutant sG145R on the HBsAg, causing 30% inhibition of virion secretion, has been identified from a study on FH strains, suggesting the potential role of defective surface antigen expression in the fulminant clinical course of HBV infection[[71]].

Mechanistically, defective surface antigen expression, such as specific mutations in the preS/S gene, may lead to secretion defects of viral proteins and particles, resulting in an accumulation of viral products in the ER of hepatocytes and causing ER stress and hepatocyte injury[[16]]. Subsequently, autophagy may be triggered[[117]-[125]] and thus enhance HBV replication[[126],[127]]. Consistent with this speculation, it has been demonstrated that defective surface antigen expression may increase the replication capability of HBV, albeit the mechanism is still undefined[[71],[84]]. In addition, the deficiency of hepadnavirus envelope proteins can result in accumulation of cccDNA[[85],[87],[88]] or deproteinized rcDNA[[89]-[91]] and may ultimately cause death of the infected hepatocytes by a direct cytopathic effect[[85],[87],[88]]. Meanwhile, the increase of the cccDNA level may facilitate HBV replication. Both the defect in viral particle secretion and enhanced replication competence may contribute to the severity of fulminant hepatitis[[128]].

The adaptive immune response, particularly the cytotoxic T lymphocyte (CTL) response, plays a crucial role in viral clearance and disease pathogenesis of HBV infection[[129]-[131]]. Intracellular retention of HBV surface proteins was found to be associated with FH in a transgenic mouse model showing panlobular necrosis and hepatic failure by inducing the indirect cytotoxic activity of CTLs[[132]]. In this setting, intracellular accumulation of viral products due to defective surface antigen expression mutations may cause liver damage through abnormal activation of the CTL response. Consistently, we also observed significantly stronger intrahepatic CTL responses and antibody responses specific to secretion-deficient HBsAg due to preS deletions[[84]]. A preS deletion mutant was found in a patient with acute exacerbation of liver diseases, along with wild-type HBV genomes. The co-existence of deletion mutants and wild-type HBV apparently allows the complementation and enhancement of HBV genome replication in hepatocytes. In an HBV mouse model, co-replication of a deletion mutant and wild-type HBV induced higher cellular and humoral immunity. Our findings further suggested the proposed role of HBV variants in the immunopathogenesis of HBV infection. Moreover, the mutations associated with defective surface antigen expression, such as deletion or missense mutation of the preS2 ATG codon, can cause deletions or alterations of B- and T-cell epitopes located in preS1 and preS2 proteins. Considering that M protein-specific T- and B-cell immunities are important early events in the host immune response to HBV infection[[43]], these mutations may lead to an immune evasion and thus likely favor a more severe clinical course of infection[[14],[133]]. In chronic HBV infection, high HBV replication levels were found to be associated with lower cellular immune responses to HBV; however, massive infiltration of unspecific immune cells occurred within the liver, accompanied by severe liver damage[[134]-[136]]. Thus, the presence of these mutations, including aa substitutions at the immunodominant epitopes for B or T cell recognition, may contribute to the spread of highly replicative escape mutants. It may also facilitate the development of fulminant hepatitis in chronically HBV-infected patients and heavily immunocompromised patients, like those with human immunodeficiency virus (HIV) co-infection[[137]] (Figure 2).

Figure 2

The proposed pathogenic role of mutated secretion-defective hepatitis B surface antigen in fulminant hepatitis. Defective surface antigens, such as preS deletions and mutations within the “a” determinant, may lead to secretion deficiency of HBsAg. Defective HBsAg can promote covalently closed circular DNA (cccDNA) synthesis and amplification, thus facilitating HBV replication. The intracellular accumulation of defective HBsAg can cause endoplasmic reticulum (ER) stress, subsequently trigger autophagy, and may further enhance HBV replication. The enhanced HBV replication, in turn, leads to accumulation of more defective HBsAg, possibly resulting in a positive feedback with unfavorable outcomes and hepatocyte damages. Inflammation may occur in the liver by recruiting immune cells. Cytotoxic T lymphocyte (CTL) response may be abnormally activated and damage infected hepatocytes, contributing to the progression of fulminant hepatitis. HBsAg: Hepatitis B surface antigen.

Defective surface antigen expression and occult hepatitis B virus infection

Occult HBV infection (OBI) is characterized by the presence of very low levels of HBV DNA in the plasma and/or liver of individuals negative for HBV surface antigen (HBsAg) and positive/negative for antibodies to the hepatitis core antigen (anti-HBc)[[45],[138],[139]]. OBI harbors the potential risk of HBV transmission through blood transfusion, organ transplantation, and hemodialysis as well as from occult infection or HBsAg-positive mothers to newborns[[45]]. The persistence of OBI may lead to the development of cirrhosis and HCC[[45],[140]-[145]]. The reactivation of OBI can occur in patients following chemotherapy, immunosuppressive therapy, and after transplantation as well as in patients co-infected with HIV or hepatitis C virus (HCV)[[45],[146],[147]], which can result in the development of fulminant hepatitis and death[[139],[148]-[153]].

Defective surface antigen expression mutations may be associated with OBI. Point mutations and deletions as well as insertion mutations are commonly encountered in OBI, in which mutations in the preS/S gene are the most extensively studied[[45]]. High frequencies of MHR mutations, including those mutations within and outside of the a-determinant, have been observed in OBI strains of individuals[[154]-[158]]. In vitro and in vivo experiments have demonstrated that these MHR mutations can significantly decrease the detection sensitivity of commercial HBsAg immunoassays and impair virion and/or S protein secretion[[156]]. preS/S mutations with deletions covering the preS1 and preS2/S promoters, preS1 region, and preS2 region have been frequently reported in OBI. This can alter the transcription of 2.4 kb and 2.1 kb HBV RNAs, expression of three envelope proteins, and the ratio of LHBs/MHBs/SHBs proteins[[45]]. preS/S insertions, such as 2-8 aa insertions between codons 121 and 124 located upstream of the a-determinant, have also been observed in OBI patients[[159]].

On one hand, these mutations associated with defective surface antigen expression can directly decrease the levels of surface antigens. On the other hand, these mutations can cause the retention and accumulation of HBsAg within cells and impair the secretion of HBsAg by altering the ratio of LHBs/MHBs/SHBs proteins[[72],[73],[160],[161]]. Therefore, circulating HBsAg levels are low in the peripheral blood. Moreover, it is well documented that neutralizing antibodies produced during natural infection, or following active or passive immunization against HBV, are targeted to the conformational epitopes of the a-determinant[[162]]. Hence, single or multiple mutations occurring within this region can lead to conformational changes with impaired antigenicity[[72],[160]]. A recent report has identified novel SHBs mutations outside the MHR from untreated CHB patients. These mutations impaired virion secretion and caused lower binding affinity to antibodies used for HBsAg immunoassays[[163]]. For these reasons, the mutations can render HBsAg undetectable or poorly detected by immunoassays based on monoclonal antibodies against wild-type virus[[60],[62],[65],[164]], contributing to some cases of OBI[[165]-[170]] (Figure 3).

Figure 3

The relationship between the expression of defective surface antigens and occult hepatitis B virus infection. Surface antigen mutations, such as preS deletions, can impair the transcription of 2.4 and 2.1 kb HBV RNAs, leading to decreased levels of three HBV surface proteins. In addition, defective surface antigens with preS deletions and mutations within the “a” determinant are secretion deficient. Single or multiple mutations occurring within the MHR between the aa residues 99-169 of SHBs, especially those within the “a” determinant between aa 124-147, can lead to conformational changes of HBsAg. Mutated HBsAg is poorly detected by immunoassays based on monoclonal antibodies, contributing to some cases of OBI. OBI: Occult hepatitis B virus infection; HBsAg: Hepatitis B surface antigen.


Defective surface antigen expression has been well documented to be relevant for the progression of HBV-associated liver diseases, such as HCC. However, the role of defective surface antigen expression in FH still needs to be clarified in future research, particularly, using in vivo models and in patients. The exact molecular mechanisms of how defective HBV surface antigens cause damage to hepatocytes and induce liver injury and subsequent pathogenic processes should be investigated. A deep understanding of the molecular mechanisms of HBV pathogenesis related to defective surface antigens is crucial to designing future therapeutic approaches. A critical question would be whether currently used nucleotide analogues (NAs) and interferon-based therapies can prevent such pathogenic processes. NAs are able to efficiently inhibit HBV DNA synthesis but not gene expression. Thus, HBV proteins, including surface antigens, are continuously produced under NA therapies. Another problem is the production of mutated HBV proteins from integrated HBV DNA, which are not controlled by NA therapies at all. Thus, specific interventions may be required to block the pathogenic potential of HBV proteins, besides efficient inhibition of HBV DNA synthesis. RNA silencing may be a suitable choice to achieve this goal[[5],[6],[171],[172]].

An additional issue to be addressed is whether the defective surface antigen-related mutations may represent novel biomarkers of OBI. With improvement of HBV antigen and DNA detection assays, OBI will likely be easier to diagnose in the future. However, the question remains whether OBI may be related to significant HBV pathogenesis and require therapeutic interventions, such as prophylaxis and antiviral therapy, to prevent HBV reactivation[[173]].


  1. JJ OttGA StevensJ GroegerST WiersmaGlobal epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicityVaccine2012302212221922273662
  2. Polaris Observatory CollaboratorsGlobal prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling studyLancet Gastroenterol Hepatol2018338340329599078
  3. D GlebeCM BremerThe molecular virology of hepatitis B virusSemin Liver Dis20133310311223749666
  4. W BernalG AuzingerA DhawanJ WendonAcute liver failureLancet201037619020120638564
  5. AS LokF ZoulimG DusheikoMG GhanyHepatitis B cure: From discovery to regulatory approvalHepatology2017661296131328762522
  6. AS LokF ZoulimG DusheikoMG GhanyHepatitis B cure: From discovery to regulatory approvalJ Hepatol20176784786128778687
  7. AD KosinskaJ LiuM LuM RoggendorfTherapeutic vaccination and immunomodulation in the treatment of chronic hepatitis B: preclinical studies in the woodchuckMed Microbiol Immunol201520410311425535101
  8. C SeegerWS MasonMolecular biology of hepatitis B virus infectionVirology2015479-48067268625759099
  9. M NassalHBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis BGut2015641972198426048673
  10. C SeegerControl of viral transcripts as a concept for future HBV therapiesCurr Opin Virol201830182329453098
  11. S TongP RevillOverview of hepatitis B viral replication and genetic variabilityJ Hepatol201664S4S1627084035
  12. WH GerlichMedical virology of hepatitis B: how it began and where we are nowVirol J20131023923870415
  13. CL LinJH KaoHepatitis B virus genotypes and variantsCold Spring Harb Perspect Med20155a02143625934462
  14. A KayF ZoulimHepatitis B virus genetic variability and evolutionVirus Res200712716417617383765
  15. JH KaoPJ ChenDS ChenRecent advances in the research of hepatitis B virus-related hepatocellular carcinoma: epidemiologic and molecular biological aspectsAdv Cancer Res2010108217221034965
  16. T PollicinoI CacciolaF SaffiotiG RaimondoHepatitis B virus PreS/S gene variants: pathobiology and clinical implicationsJ Hepatol20146140841724801416
  17. T ShenXM YanHepatitis B virus genetic mutations and evolution in liver diseasesWorld J Gastroenterol2014205435544124833874
  18. ZH ZhangCC WuXW ChenX LiJ LiMJ LuGenetic variation of hepatitis B virus and its significance for pathogenesisWorld J Gastroenterol20162212614426755865
  19. BF ChenCJ LiuGM JowPJ ChenJH KaoDS ChenHigh prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseasesGastroenterology20061301153116816618410
  20. KH HeermannU GoldmannW SchwartzT SeyffarthH BaumgartenWH GerlichLarge surface proteins of hepatitis B virus containing the pre-s sequenceJ Virol1984523964026492255
  21. R CattaneoH WillN HernandezH SchallerSignals regulating hepatitis B surface antigen transcriptionNature19833053363386621688
  22. W StibbeWH GerlichStructural relationships between minor and major proteins of hepatitis B surface antigenJ Virol1983466266286842680
  23. V SchlüterM MeyerPH HofschneiderR KoshyWH CaselmannIntegrated hepatitis B virus X and 3’ truncated preS/S sequences derived from human hepatomas encode functionally active transactivatorsOncogene19949333533447936659
  24. YW LiFC YangHQ LuJS ZhangHepatocellular carcinoma and hepatitis B surface proteinWorld J Gastroenterol2016221943195226877602
  25. J Le SeyecP ChouteauI CannieC Guguen-GuillouzoP GriponInfection process of the hepatitis B virus depends on the presence of a defined sequence in the pre-S1 domainJ Virol199973205220579971786
  26. A SchulzeP GriponS UrbanHepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycansHepatology2007461759176818046710
  27. D GlebeS UrbanEV KnoopN CagP KrassS GrünA BulavaiteK SasnauskasWH GerlichMapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytesGastroenterology200512923424516012950
  28. D GlebeM AliakbariP KrassEV KnoopKP ValeriusWH GerlichPre-s1 antigen-dependent infection of Tupaia hepatocyte cultures with human hepatitis B virusJ Virol2003779511952112915565
  29. H YanG ZhongG XuW HeZ JingZ GaoY HuangY QiB PengH WangSodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virusElife20121e0004923150796
  30. P OstapchukP HearingD GanemA dramatic shift in the transmembrane topology of a viral envelope glycoprotein accompanies hepatitis B viral morphogenesisEMBO J199413104810578131739
  31. V BrussX LuR ThomssenWH GerlichPost-translational alterations in transmembrane topology of the hepatitis B virus large envelope proteinEMBO J199413227322798194518
  32. V BrussHepatitis B virus morphogenesisWorld J Gastroenterol200713657317206755
  33. T GarciaJ LiC SureauK ItoY QinJ WandsS TongDrastic reduction in the production of subviral particles does not impair hepatitis B virus virion secretionJ Virol200983111521116519706705
  34. K ZhaoC WuY YaoL CaoZ ZhangY YuanY WangR PeiJ ChenX HuCeruloplasmin inhibits the production of extracellular hepatitis B virions by targeting its middle surface proteinJ Gen Virol2017981410142128678687
  35. V BrussD GanemThe role of envelope proteins in hepatitis B virus assemblyProc Natl Acad Sci USA199188105910631992457
  36. D FernholzPR GalleM StemlerM BrunettoF BoninoH WillInfectious hepatitis B virus variant defective in pre-S2 protein expression in a chronic carrierVirology19931941371488480417
  37. D GanemAM PrinceHepatitis B virus infection--natural history and clinical consequencesN Engl J Med20043501118112915014185
  38. DH PersingHE VarmusD GanemInhibition of secretion of hepatitis B surface antigen by a related presurface polypeptideScience1986234138813913787251
  39. JH OuWJ RutterRegulation of secretion of the hepatitis B virus major surface antigen by the preS-1 proteinJ Virol1987617827863806798
  40. FV ChisariP FilippiA McLachlanDR MilichM RiggsS LeeRD PalmiterCA PinkertRL BrinsterExpression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic miceJ Virol1986608808873783819
  41. FV ChisariP FilippiJ BurasA McLachlanH PopperCA PinkertRD PalmiterRL BrinsterStructural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic miceProc Natl Acad Sci USA198784690969133477814
  42. R NayersinaP FowlerS GuilhotG MissaleA CernyHJ SchlichtA VitielloR ChesnutJL PersonAG RedekerHLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infectionJ Immunol1993150465946717683326
  43. FV ChisariC FerrariHepatitis B virus immunopathogenesisAnnu Rev Immunol19951329607612225
  44. N CoppolaL OnoratoC MinichiniG Di CaprioM StaraceC SagnelliE SagnelliClinical significance of hepatitis B surface antigen mutantsWorld J Hepatol201572729273926644816
  45. HL ZhuX LiJ LiZH ZhangGenetic variation of occult hepatitis B virus infectionWorld J Gastroenterol2016223531354627053845
  46. P MaupasJP ChironF BarinP CoursagetA GoudeauJ PerrinF DenisID MarEfficacy of hepatitis B vaccine in prevention of early HBsAg carrier state in children. Controlled trial in an endemic area (Senegal)Lancet198112892926109938
  47. W SzmunessCE StevensEJ HarleyEA ZangWR OleszkoDC WilliamR SadovskyJM MorrisonA KellnerHepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United StatesN Engl J Med19803038338416997738
  48. P ValenzuelaA MedinaWJ RutterG AmmererBD HallSynthesis and assembly of hepatitis B virus surface antigen particles in yeastNature19822983473507045698
  49. S ReignatGJ WebsterD BrownGS OggA KingSL SeneviratneG DusheikoR WilliamsMK MainiA BertolettiEscaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infectionJ Exp Med20021951089110111994415
  50. LG GuidottiM IsogawaFV ChisariHost-virus interactions in hepatitis B virus infectionCurr Opin Immunol201536616626186123
  51. S WangZ ChenC HuF QianY ChengM WuB ShiJ ChenY HuZ YuanHepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 production in monocytes/macrophages by interfering with JNK activationJ Immunol20131905142515123585678
  52. J LiuQ YuW WuX HuangR BroeringM WernerM RoggendorfD YangM LuTLR2 Stimulation Strengthens Intrahepatic Myeloid-Derived Cell-Mediated T Cell Tolerance through Inducing Kupffer Cell Expansion and IL-10 ProductionJ Immunol20182002341235129459406
  53. M JiangR BroeringM TripplerL PoggenpohlM FiedlerG GerkenM LuJF SchlaakToll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigenJ Viral Hepat20142186087224498958
  54. J WuZ MengM JiangR PeiM TripplerR BroeringA BucchiJP SowaU DittmerD YangHepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cellsHepatology2009491132114019140219
  55. Z FangJ LiX YuD ZhangG RenB ShiC WangAD KosinskaS WangX ZhouPolarization of Monocytic Myeloid-Derived Suppressor Cells by Hepatitis B Surface Antigen Is Mediated via ERK/IL-6/STAT3 Signaling Feedback and Restrains the Activation of T Cells in Chronic Hepatitis B Virus InfectionJ Immunol20151954873488326416274
  56. KK DietzeS SchimmerF KretzmerJ WangY LinX HuangW WuB WangM LuU DittmerCharacterization of the Treg Response in the Hepatitis B Virus Hydrodynamic Injection Mouse ModelPLoS One201611e015171726986976
  57. AD KosinskaL Pishraft-SabetW WuZ FangM LenartJ ChenKK DietzeC WangT KemperY LinLow hepatitis B virus-specific T-cell response in males correlates with high regulatory T-cell numbers in murine modelsHepatology201766698328295453
  58. AR ZanettiE TanziG ManzilloG MaioC SbregliaN CaporasoH ThomasAJ ZuckermanHepatitis B variant in EuropeLancet1988211321133
  59. WF CarmanAR ZanettiP KarayiannisJ WatersG ManzilloE TanziAJ ZuckermanHC ThomasVaccine-induced escape mutant of hepatitis B virusLancet19903363253291697396
  60. MP CooremanMH van RoosmalenR te MorscheCM SünnenEM de VenJB JansenGN TytgatPL de WitWP PaulijCharacterization of the reactivity pattern of murine monoclonal antibodies against wild-type hepatitis B surface antigen to G145R and other naturally occurring “a” loop escape mutationsHepatology1999301287129210534351
  61. MP CooremanG Leroux-RoelsWP PaulijVaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigenJ Biomed Sci2001823724711385295
  62. HL ChiouTS LeeJ KuoYC MauMS HoAltered antigenicity of ‘a’ determinant variants of hepatitis B virusJ Gen Virol199778Pt 10263926459349486
  63. S GüntherL FischerI PultM SterneckH WillNaturally occurring variants of hepatitis B virusAdv Virus Res1999522513710384235
  64. M LuT LorentzDe novo infection in a renal transplant recipient caused by novel mutants of hepatitis B virus despite the presence of protective anti-hepatitis B surface antibodyJ Infect Dis20031871323132612696014
  65. S Seddigh-TonekaboniJA WatersS JeffersR GehrkeB OfenlochA HorschG HessHC ThomasP KarayiannisEffect of variation in the common “a” determinant on the antigenicity of hepatitis B surface antigenJ Med Virol20006011312110596008
  66. MG GhanyB AyolaFG VillamilRG GishS RojterJM VierlingAS LokHepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxisHepatology1998272132229425940
  67. HY HsuMH ChangYH NiHH LinSM WangDS ChenSurface gene mutants of hepatitis B virus in infants who develop acute or chronic infections despite immunoprophylaxisHepatology1997267867919303514
  68. H OkamotoK YanoY NozakiA MatsuiH MiyazakiK YamamotoF TsudaA MachidaS MishiroMutations within the S gene of hepatitis B virus transmitted from mothers to babies immunized with hepatitis B immune globulin and vaccinePediatr Res1992322642681383917
  69. U Protzer-KnolleU NaumannR BartenschlagerT BergU HopfKH Meyer zum BüschenfeldeP NeuhausG GerkenHepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantationHepatology1998272542639425945
  70. C WuW DengL DengL CaoB QinS LiY WangR PeiD YangM LuAmino acid substitutions at positions 122 and 145 of hepatitis B virus surface antigen (HBsAg) determine the antigenicity and immunogenicity of HBsAg and influence in vivo HBsAg clearanceJ Virol2012864658466922301154
  71. T KalininaA RiuL FischerH WillM SterneckA dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitisHepatology20013438539411481624
  72. C WuX ZhangY TianJ SongD YangM RoggendorfM LuX ChenBiological significance of amino acid substitutions in hepatitis B surface antigen (HBsAg) for glycosylation, secretion, antigenicity and immunogenicity of HBsAg and hepatitis B virus replicationJ Gen Virol20109148349219812261
  73. S LiK ZhaoS LiuC WuY YaoL CaoX HuY ZhouY WangR PeiHBsAg sT123N mutation induces stronger antibody responses to HBsAg and HBcAg and accelerates in vivo HBsAg clearanceVirus Res201521011912526260331
  74. F ZoulimD DurantelAntiviral therapies and prospects for a cure of chronic hepatitis BCold Spring Harb Perspect Med20155
  75. F ZoulimS LocarniniHepatitis B virus resistance to nucleos(t)ide analoguesGastroenterology200913715931608.e1-219737565
  76. N WarnerS LocarniniThe antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral reboundHepatology200848889818537180
  77. SH AhnYK ParkES ParkJH KimDH KimKH LimMS JangWH ChoeSY KoIK SungThe impact of the hepatitis B virus polymerase rtA181T mutation on replication and drug resistance is potentially affected by overlapping changes in surface geneJ Virol2014886805681824696492
  78. CT YehDevelopment of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapyAntivir Ther20101547147520516567
  79. T PollicinoG AmaddeoA RestucciaG RaffaA AlibrandiG CutroneoA FavaloroS MaimoneG SquadritoG RaimondoImpact of hepatitis B virus (HBV) preS/S genomic variability on HBV surface antigen and HBV DNA serum levelsHepatology20125643444322271491
  80. D FernholzM StemlerM BrunettoF BoninoH WillReplicating and virion secreting hepatitis B mutant virus unable to produce preS2 proteinJ Hepatol199113 Suppl 4S102S1041822500
  81. G GerkenD KremsdorfF CapelMA PetitC DauguetMP MannsKH Meyer zum BüschenfeldeC BrechotHepatitis B defective virus with rearrangements in the preS gene during chronic HBV infectionVirology19911835555651853561
  82. F SugauchiT OhnoE OritoH SakugawaT IchidaM KomatsuT KuramitsuR UedaY MiyakawaM MizokamiInfluence of hepatitis B virus genotypes on the development of preS deletions and advanced liver diseaseJ Med Virol20037053754412794715
  83. CH ChenCS ChangchienCM LeeCH HungTH HuJH WangJC WangSN LuCombined mutations in pre-s/surface and core promoter/precore regions of hepatitis B virus increase the risk of hepatocellular carcinoma: a case-control studyJ Infect Dis20081981634164218939932
  84. L CaoC WuH ShiZ GongE ZhangH WangK ZhaoS LiuS LiX GaoCoexistence of hepatitis B virus quasispecies enhances viral replication and the ability to induce host antibody and cellular immune responsesJ Virol2014888656866624850745
  85. J SummersPM SmithAL HorwichHepadnavirus envelope proteins regulate covalently closed circular DNA amplificationJ Virol199064281928242335817
  86. RJ LenhoffJ SummersCoordinate regulation of replication and virus assembly by the large envelope protein of an avian hepadnavirusJ Virol199468456545718207830
  87. RJ LenhoffCA LuscombeJ SummersAcute liver injury following infection with a cytopathic strain of duck hepatitis B virusHepatology1999295635719918936
  88. J SummersPM SmithMJ HuangMS YuMorphogenetic and regulatory effects of mutations in the envelope proteins of an avian hepadnavirusJ Virol199165131013171995945
  89. W GaoJ HuFormation of hepatitis B virus covalently closed circular DNA: removal of genome-linked proteinJ Virol2007816164617417409153
  90. H GuoD JiangT ZhouA CuconatiTM BlockJT GuoCharacterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: an intermediate of covalently closed circular DNA formationJ Virol200781124721248417804499
  91. TB LentzDD LoebRoles of the envelope proteins in the amplification of covalently closed circular DNA and completion of synthesis of the plus-strand DNA in hepatitis B virusJ Virol201185119161192721900164
  92. SC MuYM LinGM JowBF ChenOccult hepatitis B virus infection in hepatitis B vaccinated children in TaiwanJ Hepatol20095026427219070923
  93. MM ChiraraCJ ChetsangaVariant of hepatitis B virus isolated in ZimbabweJ Med Virol19944273788308523
  94. SM BowyerL van StadenMC KewJG SimA unique segment of the hepatitis B virus group A genotype identified in isolates from South AfricaJ Gen Virol199778Pt 7171917299225049
  95. WK OwireduA KramvisMC KewMolecular analysis of hepatitis B virus genomes isolated from black African patients with fulminant hepatitis BJ Med Virol20016548549211596083
  96. RS GarfeinWA BowerCM LoneyYJ HutinGL XiaJ JawandaAV GroomOV NainanJS MurphyBP BellFactors associated with fulminant liver failure during an outbreak among injection drug users with acute hepatitis BHepatology20044086587315382123
  97. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, Lau GK, Locarnini S; Chronic Hepatitis B Guideline Working Party of the Asian-Pacific Association for the Study of the LiverAsian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 updateHepatol Int2008226328319669255
  98. T ShenXM YanYL ZouJM GaoH DongVirologic characteristics of hepatitis B virus in patients infected via maternal-fetal transmissionWorld J Gastroenterol2008145674568218837083
  99. FC ShenIJ SuHC WuYH HsiehWJ YaoKC YoungTC ChangHC HsiehHN TsaiW HuangA pre-S gene chip to detect pre-S deletions in hepatitis B virus large surface antigen as a predictive marker for hepatoma risk in chronic hepatitis B virus carriersJ Biomed Sci2009168419751529
  100. T ShenXM YanJP ZhangJL WangRX ZuoL LiLP WangEvolution of Hepatitis B Virus in a Chronic HBV-Infected Patient over 2 YearsHepat Res Treat2011201193914821785721
  101. NY HeoHC LeeYK ParkJW ParkYS LimKM KimJH ShimYJ LeeLack of association between hepatitis B virus pre-S mutations and recurrence after surgical resection in hepatocellular carcinomaJ Med Virol20138558959623296476
  102. CH HungCH ChenCM LeeTH HuSN LuJH WangCM HuangRole of viral genotypes and hepatitis B viral mutants in the risk of hepatocellular carcinoma associated with hepatitis B and C dual infectionIntervirology20135631632423838434
  103. YF FanCC LuWC ChenWJ YaoHC WangTT ChangHY LeiAL ShiauIJ SuPrevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infectionHepatology20013327728611124846
  104. CH ChenCH HungCM LeeTH HuJH WangJC WangSN LuCS ChangchienPre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patientsGastroenterology20071331466147417915220
  105. S GhoshRK MondalP BanerjeeM NandiS SarkarK DasA SantraS BanerjeeA ChowdhuryS DattaTracking the naturally occurring mutations across the full-length genome of hepatitis B virus of genotype D in different phases of chronic e-antigen-negative infectionClin Microbiol Infect201218E412E41822827722
  106. Z XuTS YenIntracellular retention of surface protein by a hepatitis B virus mutant that releases virion particlesJ Virol1996701331408523517
  107. IJ SuLH WangWC HsiehHC WuCF TengHW TsaiW HuangThe emerging role of hepatitis B virus pre-S2 deletion mutant proteins in HBV tumorigenesisJ Biomed Sci2014219825316153
  108. P ArbuthnotM KewHepatitis B virus and hepatocellular carcinomaInt J Exp Pathol2001827710011454100
  109. E HildtPH HofschneiderThe PreS2 activators of the hepatitis B virus: activators of tumour promoter pathwaysRecent Results Cancer Res199815431532910027012
  110. WH CaselmannM MeyerAS KekuléU LauerPH HofschneiderR KoshyA trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNAProc Natl Acad Sci USA199087297029742158099
  111. U LauerL WeissM LippPH HofschneiderAS KekuléThe hepatitis B virus preS2/St transactivator utilizes AP-1 and other transcription factors for transactivationHepatology19941923318276360
  112. M SterneckS GüntherJ GerlachNV NaoumovT SantantonioL FischerX RogiersH GretenR WilliamsH WillHepatitis B virus sequence changes evolving in liver transplant recipients with fulminant hepatitisJ Hepatol1997267547649126786
  113. T PollicinoAR ZanettiI CacciolaMA PetitA SmedileS CampoL SaglioccaM PasqualiE TanziG LongoPre-S2 defective hepatitis B virus infection in patients with fulminant hepatitisHepatology1997264954999252165
  114. CT BockHL TillmannHJ MaschekMP MannsC TrautweinA preS mutation isolated from a patient with chronic hepatitis B infection leads to virus retention and misassemblyGastroenterology1997113197619829394738
  115. CT BockS KubickaMP MannsC TrautweinTwo control elements in the hepatitis B virus S-promoter are important for full promoter activity mediated by CCAAT-binding factorHepatology1999291236124710094970
  116. CT BockHL TillmannMP MannsC TrautweinThe pre-S region determines the intracellular localization and appearance of hepatitis B virusHepatology19993051752510421662
  117. M OgataS HinoA SaitoK MorikawaS KondoS KanemotoT MurakamiM TaniguchiI TaniiK YoshinagaAutophagy is activated for cell survival after endoplasmic reticulum stressMol Cell Biol2006269220923117030611
  118. M Høyer-HansenM JäätteläConnecting endoplasmic reticulum stress to autophagy by unfolded protein response and calciumCell Death Differ2007141576158217612585
  119. Y KourokuE FujitaI TanidaT UenoA IsoaiH KumagaiS OgawaRJ KaufmanE KominamiT MomoiER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formationCell Death Differ20071423023916794605
  120. J LiM NiB LeeE BarronDR HintonAS LeeThe unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cellsCell Death Differ2008151460147118551133
  121. L QinZ WangL TaoY WangER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagyAutophagy2010623924720104019
  122. S LépineJC AllegoodM ParkP DentS MilstienS SpiegelSphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagyCell Death Differ20111835036120798685
  123. K SakakiJ WuRJ KaufmanProtein kinase Ctheta is required for autophagy in response to stress in the endoplasmic reticulumJ Biol Chem2008283153701538018356160
  124. T YorimitsuDJ KlionskyEndoplasmic reticulum stress: a new pathway to induce autophagyAutophagy2007316016217204854
  125. T YorimitsuU NairZ YangDJ KlionskyEndoplasmic reticulum stress triggers autophagyJ Biol Chem2006281302993030416901900
  126. D SirY TianWL ChenDK AnnTS YenJH OuThe early autophagic pathway is activated by hepatitis B virus and required for viral DNA replicationProc Natl Acad Sci USA20101074383438820142477
  127. J LiY LiuZ WangK LiuY WangJ LiuH DingZ YuanSubversion of cellular autophagy machinery by hepatitis B virus for viral envelopmentJ Virol2011856319633321507968
  128. NV NaoumovAL EddlestonHost immune response and variations in the virus genome: pathogenesis of liver damage caused by hepatitis B virusGut199435101310177926896
  129. A BertolettiC FerrariAdaptive immunity in HBV infectionJ Hepatol201664S71S8327084039
  130. LG GuidottiFV ChisariImmunobiology and pathogenesis of viral hepatitisAnnu Rev Pathol20061236118039107
  131. H PeeridogahehZ MeshkatS HabibzadehM ArzanlouJM ShahiS RostamiS GerayliR TeimourpourCurrent concepts on immunopathogenesis of hepatitis B virus infectionVirus Res2018245294329273341
  132. K AndoT MoriyamaLG GuidottiS WirthRD SchreiberHJ SchlichtSN HuangFV ChisariMechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitisJ Exp Med1993178154115548228807
  133. T MinaS Amini Bavil OlyaeeF TackeP MaesM Van RanstMR PourkarimGenomic Diversity of Hepatitis B Virus Infection Associated With Fulminant Hepatitis B DevelopmentHepat Mon201515e2947726288637
  134. A BertolettiM MainiR WilliamsRole of hepatitis B virus specific cytotoxic T cells in liver damage and viral controlAntiviral Res2003606166
  135. MK MainiC BoniCK LeeJR LarrubiaS ReignatGS OggAS KingJ HerbergR GilsonA AlisaThe role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infectionJ Exp Med20001911269128010770795
  136. A BertolettiMK MainiProtection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection?Curr Opin Immunol20001240340810899021
  137. S BagaglioL AlbarelloP BiswasC Uberti-FoppaC FortisG MorsicaVirological pattern of hepatitis B infection in an HIV-positive man with fatal fulminant hepatitis B: a case reportJ Med Case Rep2009311019946588
  138. G RaimondoJP AllainMR BrunettoMA BuendiaDS ChenM ColomboA CraxìF DonatoC FerrariGB GaetaStatements from the Taormina expert meeting on occult hepatitis B virus infectionJ Hepatol20084965265718715666
  139. M MakvandiUpdate on occult hepatitis B virus infectionWorld J Gastroenterol2016228720873427818588
  140. I CheminC TrépoClinical impact of occult HBV infectionsJ Clin Virol200534 Suppl 1S15S2116461218
  141. SJ HashemiE HajianiA MasjedizadehM MakvandiAA ShayestehSP AlavinejadA KadkhodaeiH ShahbazianF JasemiM KarimiOccult hepatitis B infection in patients with cryptogenic liver cirrhosis in southwest of IranJundishapur J Microbiol20158e1687325861432
  142. C SaittaG TripodiA BarberaA BertuccioA SmedileA CiancioG RaffaA SangiovanniG NavarraG RaimondoHepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinomaLiver Int2015352311231725677098
  143. I CheminF ZoulimP MerleA ArkhisM ChevallierA KayL CovaP ChevallierB MandrandC TrépoHigh incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiologyJ Hepatol20013444745411322208
  144. T PollicinoG SquadritoG CerenziaI CacciolaG RaffaA CraxiF FarinatiG MissaleA SmedileC TiribelliHepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infectionGastroenterology200412610211014699492
  145. DK WongFY HuangCL LaiRT PoonWK SetoJ FungIF HungMF YuenOccult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinomaHepatology20115482983621809355
  146. M AltfeldJK RockstrohM AddoB KupferI PultH WillU SpenglerReactivation of hepatitis B in a long-term anti-HBs-positive patient with AIDS following lamivudine withdrawalJ Hepatol1998293063099722213
  147. K Kidd-LjunggrenO SimonsenReappearance of hepatitis B 10 years after kidney transplantationN Engl J Med199934112712810409028
  148. TH WesthoffF JochimsenA SchmittelM Stoffler-MeilickeJH SchaferW ZidekWH GerlichE ThielFatal hepatitis B virus reactivation by an escape mutant following rituximab therapyBlood2003102193012930732
  149. S KuboA TamoriK OhbaT ShutoT YamamotoH TanakaS NishiguchiK WakasaK HirohashiH KinoshitaPrevious or occult hepatitis B virus infection in hepatitis C virus-associated hepatocellular carcinoma without hepatic fibrosisDig Dis Sci2001462408241411713944
  150. G LalazarD RundD ShouvalScreening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignanciesBr J Haematol200713669971217338776
  151. A García-FulgueirasR García-PinaC MorantV García-OrtuzarR GénovaE AlvarezHepatitis C and hepatitis B-related mortality in SpainEur J Gastroenterol Hepatol20092189590119357523
  152. P MarcellinF PequignotE Delarocque-AstagneauJP ZarskiN GanneP HillonD AntonaM BovetM MechainT AsselahMortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumptionJ Hepatol20084820020718086507
  153. M XieW RaoT YangY DengH ZhengC PanY LiuZ ShenJ JiaOccult hepatitis B virus infection predicts de novo hepatitis B infection in patients with alcoholic cirrhosis after liver transplantationLiver Int20153589790424750566
  154. D CandottiP GrabarczykP GhiazzaR RoigN CasamitjanaP IudiconeM SchmidtA BirdR CrookesE BrojerCharacterization of occult hepatitis B virus from blood donors carrying genotype A2 or genotype D strainsJ Hepatol20084953754718602718
  155. JP AllainD BelkhiriM VermeulenR CrookesR CableA AmiriR ReddyA BirdD CandottiCharacterization of occult hepatitis B virus strains in South African blood donorsHepatology2009491868187619434719
  156. CH HuangQ YuanPJ ChenYL ZhangCR ChenQB ZhengSH YehH YuY XueYX ChenInfluence of mutations in hepatitis B virus surface protein on viral antigenicity and phenotype in occult HBV strains from blood donorsJ Hepatol20125772072922634131
  157. D SahaA PalN SarkarD DasJT BlackardSK GuhaB SahaR ChakravartyOccult hepatitis B virus infection in HIV positive patients at a tertiary healthcare unit in eastern IndiaPLoS One201712e017903528591184
  158. Q YeSQ ShangW LiA new vaccine escape mutant of hepatitis B virus causes occult infectionHum Vaccin Immunother20151140741025692622
  159. J HouZ WangJ ChengY LinGK LauJ SunF ZhouJ WatersP KarayiannisK LuoPrevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriersHepatology2001341027103411679975
  160. K KweiX TangAS LokC SureauT GarciaJ LiJ WandsS TongImpaired virion secretion by hepatitis B virus immune escape mutants and its rescue by wild-type envelope proteins or a second-site mutationJ Virol2013872352235723221548
  161. S BiswasD CandottiJP AllainSpecific amino acid substitutions in the S protein prevent its excretion in vitro and may contribute to occult hepatitis B virus infectionJ Virol2013877882789223658444
  162. JN ZuckermanAJ ZuckermanMutations of the surface protein of hepatitis B virusAntiviral Res200360757814638401
  163. KH XiangE MichailidisH DingYQ PengMZ SuY LiXE LiuVL Dao ThiXF WuWM SchneiderEffects of amino acid substitutions in hepatitis B virus surface protein on virion secretion, antigenicity, HBsAg and viral DNAJ Hepatol20176628829627650283
  164. JA WatersM KennedyP VoetP HauserJ PetreW CarmanHC ThomasLoss of the common “A” determinant of hepatitis B surface antigen by a vaccine-induced escape mutantJ Clin Invest199290254325471281839
  165. S ShahmoradiY YahyapourM MahmoodiSM AlavianZ FazeliSM JazayeriHigh prevalence of occult hepatitis B virus infection in children born to HBsAg-positive mothers despite prophylaxis with hepatitis B vaccination and HBIGJ Hepatol20125751552122617152
  166. D JeantetI CheminB MandrandA TranF ZoulimP MerleC TrepoA KayCloning and expression of surface antigens from occult chronic hepatitis B virus infections and their recognition by commercial detection assaysJ Med Virol20047350851515221893
  167. GY MinukDF SunJ UhanovaM ZhangS CaouetteLE NicolleA GutkinK DoucetteB MartinA GiuliviOccult hepatitis B virus infection in a North American community-based populationJ Hepatol20054248048515763333
  168. JR WandsRA MarciniakKJ IsselbacherM VargheseG DonJW HallidayLW PowellDemonstration of previously undetected hepatitis B viral determinants in an Australian Aboriginal population by monoclonal anti-hbs antibody radioimmunoassaysLancet198219779806176820
  169. KM WeinbergerT BauerS BöhmW JilgHigh genetic variability of the group-specific a-determinant of hepatitis B virus surface antigen (HBsAg) and the corresponding fragment of the viral polymerase in chronic virus carriers lacking detectable HBsAg in serumJ Gen Virol2000811165117410769057
  170. HL ZaaijerP TorresA OntañónLG PonteMH KoppelmanPN LelieFJ HemertHJ BootMultiple surface antigen mutations in five blood donors with occult hepatitis B virus infectionJ Med Virol2008801344134918551607
  171. RG GishMF YuenHL ChanBD GivenCL LaiSA LocarniniJY LauCI WooddellT SchluepDL LewisSynthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intentAntiviral Res20151219710826129970
  172. T SchluepJ LickliterJ HamiltonDL LewisCL LaiJY LauSA LocarniniRG GishBD GivenSafety, Tolerability, and Pharmacokinetics of ARC-520 Injection, an RNA Interference-Based Therapeutic for the Treatment of Chronic Hepatitis B Virus Infection, in Healthy VolunteersClin Pharmacol Drug Dev2017635036227739230
  173. M ZobeiriOccult hepatitis B: clinical viewpoint and managementHepat Res Treat2013201325914823533738
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