Hepatitis B is a major public health problem; it affects over 250 million people worldwide, and 850,000 deaths occur each year as a result of hepatitis B complications. The structure of its etiological agent, the hepatitis B virus (HBV), features a nucleocapsid that is surrounded by a lipid bilayer containing the HBV surface antigen (HBsAg) consiting in three envelope glycoproteins (GPs) designated as small (S), medium (M), and large (L), which are the products of a single open reading frame. They share the C-terminal S domain that contains four putative transmembrane (TM) domains. The L and M proteins have N-terminal extensions (preS1/preS2 and preS2, respectively) that mediate diverse functions in nucleocapsid binding and receptor recognition (Baumert et al., 2014). The first 2- to 75-amino-acid sequence of the preS1 domain of the L protein (Blanchet and Sureau, 2007; Bremer et al., 2011; Le Seyec et al., 1999) and the antigenic loop (AGL) of the S domain (Le Duff et al., 2009; Salisse and Sureau, 2009; Schulze et al., 2007) have been identified as essential determinants for infectivity of HBV and hepatitis delta virus (HDV), a pathogen that depends on HBV GPs for its propagation.

Entry of enveloped viruses into cells can be defined as the sequence of events occurring from the attachment of the virus to the host cell until the release of the genome into the cytoplasm, via fusion between viral and cellular membranes. Like for most enveloped viruses, HBV entry into cells is a finely regulated and complex process consisting of different steps, in which several viral and cellular factors are involved. Its first step involves low-affinity binding to heparan sulfate proteoglycans (HSPGs) residing on the hepatocytes’ surface (Leistner et al., 2008; Schulze et al., 2007). This attachment is mediated by the preS1 region of the L protein and/or the AGL of the S protein (Ni et al., 2014; Schulze et al., 2007). Afterwards, the virus interacts with its high-affinity receptor, the sodium taurocholate-cotransporting polypeptide (NTCP) (Ni et al., 2014; Yan et al., 2012), through the amino-terminal end of the L protein preS1 domain (Glebe et al., 2005; Gripon et al., 2005; Yan et al., 2012). NTCP is an integral membrane protein expressed at the basolateral membrane of hepatocytes, which explains the tropism of HBV for the liver.

The post-binding entry steps of HBV occur through endocytosis; however, the exact mechanism is still unclear and somehow controversial. One early study in HepaRG cells showed that HBV is internalized via caveolin-mediated endocytosis (Macovei et al., 2010). Nevertheless, inhibition of caveolin-mediated endocytosis or silencing of caveolin-1 did not impair HBV infection in tupaia hepatocytes (Bremer et al., 2009) or in HepaG2-NTCP cells (Herrscher et al., 2020). Contrastingly, several other studies presented evidence that HBV endocytosis is clathrin-dependent (Herrscher et al., 2020; Huang et al., 2012; Umetsu et al., 2018). Recent studies have reported that HBV infection of HepaRG cells depends on Rab5 and Rab7 (Macovei et al., 2013), which are GTPases involved in the biogenesis of endosomes, and that the epidermal growth factor receptor (EGFR) is a host-entry cofactor that interacts with NTCP and mediates HBV internalization (Iwamoto et al., 2019). These findings support the hypothesis that HBV is transported from early to mature endosomes. After the early endosome stage, translocation is associated with a gradually decreasing pH, from about 6.2 in early endosomes to close to 5.5 in late endosomes, which allows fusion of many enveloped viruses with the endosomal membrane. However, in the case of HBV, pharmacological agents that raise or neutralize the pH in the endocytic pathway do not affect infection (Macovei et al., 2010; Macovei et al., 2013; Rigg and Schaller, 1992). Furthermore, treatments with protease inhibitors have no effect on infection (Macovei et al., 2013), suggesting that HBV transport into the degradative branch of the endocytic pathway is not required per se to initiate this process.

Virus entry by membrane fusion involves interactions between viral fusion proteins and host receptors, which result in conformational changes of the virus envelope proteins. However, the molecular determinants and mechanism of membrane fusion of HBV remain to be defined. Previous results have indicated the essential role of the cysteine residues of the AGL, as shown by the reduction of virus entry levels by inhibitors of thiol/disulfide exchange reaction (Abou-Jaoudé and Sureau, 2007), hence suggesting a redox state responsible for conformational changes that can have a role during the fusion step.

Here, using a combination of computational and experimental approaches, we sought to better understand how HBV induces the fusion of its lipid membrane with that of the infected cell. Specifically, using a coevolution analysis of HBV GPs and molecular modeling combined with experimental investigations ex vivo in molecular virology and in vivo in liver humanized mice, we provide evidence that the mechanism triggering HBV membrane fusion involves ERp57, a cellular protein disulfide isomerase (PDI). Furthermore, our results highlight the role of specific cysteines in the AGL determinant as well as a sequence (aa 48–66) in the preS1 determinant that could ultimately act as a fusion peptide mediating HBV membrane fusion.

The entry process of enveloped viruses into cells is the series of all events that take place from the attachment of the virus to the host cell until the release of its genome into the cytoplasm. It is a finely regulated and complex process with several steps, in which many viral and cellular factors are involved. The first interaction often occurs with HSPGs. It may lack specificity but serves to give a virus an initial catch hold from which it can recruit specific receptors and entry co-factors that drive the reactions leading to entry. Fusion is the last step of enveloped virus entry and allows the release of the viral capsid into the cytoplasm following the merging of the viral membrane with the membrane of the infected cell. The interactions with the target cell that trigger conformational changes of the viral surface glycoproteins, ultimately leading to the insertion of their fusion peptide into the cell membrane, vary widely for enveloped viruses and can be divided into different scenarios. In the first one (e.g., human immunodeficiency virus), fusion is triggered directly by the interaction of the viral glycoprotein with its cellular receptor, through allosteric conformational rearrangements. In some cases, a sequential interaction with additional host factors is required to trigger the conformational changes required for fusion. In the second scenario (e.g., influenza virus), the interactions with the receptor at the cell surface leads to the endocytosis of viral particles, which is followed by GP protonation in the low-pH environment of the intracellular endosomal organelles that triggers the fusogenic conformational change. In the third scenario (e.g., Ebola virus), the initial interactions of the virion with the cell surface trigger its endocytosis followed by a second interaction with an internal receptor, often found in late endosomes, which is preceded by proteolytic cleavage of the fusion protein by an endosomal protease, leading to fusion activation (Harrison, 2015; White and Whittaker, 2016). Finally, for certain viruses (e.g., Sindbis virus), the fusion protein requires an activating redox reaction involving disulfide bonds of their glycoproteins to induce membrane fusion (Key et al., 2015; Rey and Lok, 2018).

Using a cell-cell fusion assay, we found that HBV fusion activity reached similar levels whether indicator cells expressed or not HSPG and/or NTCP but was not increased when the cell co-cultures were exposed at low pH, in contrast to bona fide pH-dependent GPs such as VSV-G or CCHFV Gn/Gc (Figure 1). That both HSPG and NTCP, which are respectively HBV virion membrane capture molecules (Leistner et al., 2008; Schulze et al., 2007) and specific entry factors (Ni et al., 2014; Yan et al., 2015), are not required for cell-cell fusion highlights that this fusion assay reveals late entry events, such as those occurring after virus interaction with either factor. Similarly, for other viruses such as influenza virus or hepatitis C virus (HCV), binding to their cell entry receptor is not a requirement in both cell-cell fusion (Lin and Cannon, 2002) and liposome fusion (Lavillette et al., 2006) assays triggered by a low-pH treatment. Thus, while it is clear that cell-cell fusion does not recapitulate per se all the events required to promote cell entry of viral particles since it bypasses the step of internalization that subsequently allows membrane fusion in endosomes that are required for entry of the above-mentioned viruses and of HBV (Macovei et al., 2013; Iwamoto et al., 2019), it is a suitable experimental tool for investigating some of the structural and functional determinants that promote envelope glycoprotein membrane-fusion activity (Earp et al., 2004). Accordingly, our results indicate that the trigger for the HBV membrane fusion mechanism not only is independent of an allosteric interaction of its GPs with the NTCP receptor but also is independent of GP protonation that is induced by the low-pH environment of endosomes. That low pH does not increase HBV cell-cell fusion agrees with previous results indicating that pharmacological agents that raise or neutralize the pH of the endocytic pathway had no effect on HBV infection (Macovei et al., 2010; Macovei et al., 2013; Rigg and Schaller, 1992).

Previous results from Abou-Jaoudé and Sureau, 2007 showed that cysteine residues of the HBV antigenic loop are essential for HDV infectivity and that viral entry is blocked by inhibitors of thiol/disulfide exchange reaction. Our results extend this notion as they indicate that such reactions seem to be necessary to mediate a critical early post-binding event but not at a later stage of the infection process since no effect in virus infectivity could be detected when DTNB was added at 4 hr post-infection (Figure 3). Since isomerization of disulfide bonds has been shown to be crucial for conformational rearrangements of GPs from other enveloped viruses leading to fusion (Fenouillet et al., 2007), we sought to investigate if and how such reactions could be implicated during the membrane fusion step of HBV entry. Here, using our cell-cell fusion assay, we found that DTNB blocked HBV GP-mediated membrane fusion (Figure 3B). Altogether, these results indicated a role of disulfide bond network of S GP during HBV membrane fusion.

Capitalizing on the above-mentioned experimental information that inhibitors of thiol/disulfide exchange reactions alter virus entry, we sought to examine how disulfide bonds of the HBV GPs, or rather, how a potential reshuffling of its disulfide bond profile, could be important for HBV entry. Indeed, cross-strand disulfides occurring in some viral surface GPs are believed to play a role in virus entry (Barbouche et al., 2003; Jain et al., 2007; Rosenthal et al., 1998; Wouters et al., 2004). Particularly, allosteric disulfide bonds can modulate the activity of the proteins in which they reside by mediating a structural change when they are reduced or oxidized (Hogg, 2003; Schmidt et al., 2006). Allosteric control of protein function is defined as a change in one site (the allosteric site) that influences another site by exploiting the protein’s flexibility; an allosteric disulfide bond represents the ‘allosteric site’ and the conformational change triggered by cleavage of such bonds alters protein function. For the HBV S protein, we used the contact prediction method RaptorX (Ma et al., 2015; Wang et al., 2017) to predict contacts between four Cys-rich regions of the AGL determinant (Figure 4), which highlighted that two of these regions may likely interact, that is, the Cys-rich regions III and IV (Figure 4—figure supplement 1). Using the secondary structure prediction method JPred (Cole et al., 2008), we proposed that these regions organize in two β-strands and we constructed a three-dimensional model of the region 294–317 of the HBV S GP, which indicated that this sequence is compatible with a β-hairpin structural motif containing a CSD bond between C301 and C310 (Figure 4). Interestingly, the analysis of the signs of the five χ dihedral angles defined by the Cys residues allowed to classify this particular disulfide bond in a -H Staple conformation, which is a particular type of disulfide geometry associated with allosteric functions that is known to trigger conformational changes upon switching between the reduced and oxidized states (Chiu and Hogg, 2019; Schmidt et al., 2006). Hence, we hypothesized that the redox state of the C301-C310 disulfide bond may act as an allosteric switch controlling conformational rearrangements of the HBV GP leading, ultimately, to exposure of the fusion peptide. Of note, the β-hairpin region with the predicted CSD lies at the surface of the S protein according to a three-dimensional in silico model (van Hemert et al., 2008), which may allow interactions with other HBsAg subunits and/or cellular factors. Yet, to test our structural and dynamic model involving a C301-C310 CSD bond in S GP (Figure 4), we reasoned that creating an additional, neighboring disulfide bond between positions 303 and 308 may stabilize the β-hairpin motif (Figure 4), which may prevent molecular rearrangements and, thus, allow membrane fusion to occur. The in silico analysis indicates that the T303C/G308C double mutant most probably generates two structural CSD according to our JPred-based (Cole et al., 2008) structural modeling, which affects the structural conformation of the C301-C310 CSD that is no longer classified as an allosteric bond. When we tested the T303C/G308C mutation in functional assays, we found that the mutant HBV GPs induced an almost complete loss of infection and fusion activity (Figure 5), hence suggesting that by stabilizing cross-strand disulfide exchange, the putative additional disulfide bond prevented conformational rearrangements of HBV GPs that are required for promoting membrane fusion. One possibility is that such stabilization could prevent an isomerization of the C301-C310 CSD bond that generates alternative disulfide bond(s), for example, between C284 and C310, which was proposed in a previous study (Mangold et al., 1995). Yet, the antigenic loss of S induced by these mutations did not allow us to design an assay that would detect the additional disulfide bond in the T303C-G308C mutant nor the block of conformational rearrangements that is suggested by its phenotype.

Assuming that the isomerization of the C301-C310 allosteric CSD or of other thiols/disulfides of the AGL determinant could facilitate the conformational rearrangements of HBV GPs required to promote membrane fusion, we hypothesized that such an isomerization could be induced by a host factor from the PDI family, which are enzymes that can both reduce and oxidize disulfide bonds. PDIs consist of a family of 21 structurally related proteins with a thioredoxin-like domain. Most of these isomerases have a CXXC motif that catalyzes formation, reduction, and rearrangement of the disulfide bonds in proteins (Abell and Brown, 1993). These isomerases are primarily involved in the folding of proteins in the endoplasmic reticulum (ER), catalyzing formation of their disulfide bonds, and most of these isomerases have ER retention signals. However, some isomerases from the PDI family have also been shown to be present at the cell surface, both in functional and in biochemical assays (Turano et al., 2002). Accordingly, cell-surface-localized PDIs are involved in processes such as cell adhesion, nitric oxide signaling, and cell entry of different viruses (Diwaker et al., 2013; Fenouillet et al., 2007). In support of the notion that PDIs are involved in HBV entry, we found that inhibitors that target different PDI members could block infection and cell-cell fusion though not the binding of viral particles to the cell surface. Of note, we found that bacitracin, which targets PDIA1, did not inhibit HBV entry and membrane fusion, in line with a previous study showing that it could not inhibit HDV entry (Abou-Jaoudé and Sureau, 2007). While the above ruled out PDIA1 as an entry co-factor of HBV, we found a strong reduction in the levels of HBV and HDV infection as well as of HBV-induced cell-cell fusion when we used the NTZ and EGCG inhibitors (Figure 6), which target ERp57 (Müller et al., 2008; Pacello et al., 2016). Consistently, we detected a low but significant expression of ERp57 as well as of ERp46 and ERp72 at the cell surface (Figure 7), in agreement with a previous study (Turano et al., 2002). Furthermore, we detected ERp57 in late endosomes (Figure 8), which is meaningful since previous reports have shown that HBV infection of HepaRG cells depends on Rab5 and Rab7 (Macovei et al., 2013), which are GTPases involved in the biogenesis of endosomes, and that the epidermal growth factor receptor is a host-entry cofactor that interacts with NTCP and mediates HBV internalization (Iwamoto et al., 2019). Using a gene silencing approach, we confirmed that down-regulation of ERp57 but not of these alternative PDIs could decrease the levels of HDV and HBV infection as well as of cell-cell fusion (Figure 7). Importantly, we showed that a short-time treatment of liver humanized mice with NTZ could delay HBV infection by approximately 2–4 weeks (Figure 9). Since NTZ has a short half-life of about 1.5 hr in vivo (Ruiz-Olmedo et al., 2017; Stockis et al., 1996) and since NTZ was administrated at very short times before and after HBV inoculation, we calculated that less than 10% of the drug was still present in those mice at 7 hr post-infection, which likely precludes an effect on HBV post-entry steps (Korba et al., 2008). Altogether, these results support the role of ERp57 at early steps of HBV infection and validate this PDI as a therapeutic target. Note that our results did not discard the possibility that some other PDIs could also play a role during HBV entry into cells.

The fusion-mediating GPs of enveloped viruses contain a sequence, termed fusion peptide, that interacts with and destabilizes the cellular target membrane. Such an event is finely controlled so as to occur at the appropriate time and location and to prevent fortuitous inactivation of GP fusion activity and virus infectivity. Hence, a conformational change in these GPs is a requirement to induce the accessibility and function of the fusion peptide segment. Candidate fusion peptides are generally identified as hydrophobic sequences, of approximately 16–26 residues in length, that are conserved within a virus family and that may adopt α-helical conformation with strongly hydrophobic faces. They can be internal or located at the amino-terminus of fusion GP subunits (Apellániz et al., 2014; Epand, 2003; Martin et al., 1999). There are a number of criteria that characterize fusion peptide segments and, while none of these criteria taken individually are absolute to define a fusion peptide segment, they are sufficiently restrictive to predict if a given region of a protein presents features of a fusion peptide segment (Delos and White, 2000; Delos et al., 2000), which needs to be further functionally tested.

Previously, a conserved peptide comprising 23 amino acids at the N-terminal end of the HBV S protein and overlapping its TM1 sequence was shown to interact with model membranes, causing liposome destabilization in a pH-dependent manner (Berting et al., 2000; Rodríguez-Crespo et al., 1994; Rodríguez-Crespo et al., 1995; Rodríguez-Crespo et al., 1999). However, it was also demonstrated that hydrophobic residues in TM1 were critical for S protein expression as well as for infectivity (Siegler and Bruss, 2013). An essential role of TM1 in fusion mechanism, albeit in a pH-independent manner, could be shown for the duck hepatitis B virus (DHBV) (Chojnacki et al., 2005; Grgacic and Schaller, 2000), although there is also evidence for the involvement of the preS domain of DHBV at an early step of infection, likely during the fusion process (Delgado et al., 2012).

Here, through a computational hydropathy analysis of the HBV GPs, we identified two potential short sequences within the preS1 and preS2 regions that may potentially interact with membrane bilayers. To validate these predictions, we characterized in both infection and cell-cell fusion assays HBV GP mutants in key positions in either sequence. We found that while none of the mutations in the preS2 segment altered infection or membrane fusion activities, mutations in the preS1 sequence induced an almost complete loss of infectivity and cell-cell fusion (Figure 2). Note that these mutants had similar if not identical levels of cell-surface-expressed L, M, and S proteins and/or capacity to induce the formation of HDV particles. These results suggested that the preS1 region harbors a fusion peptide in addition to the NTCP-binding determinant.

Overall, our study characterizes some crucial determinants of HBV entry and membrane fusion. The mechanism by which fusion proteins are activated and undergo conformational rearrangements or fusion intermediates is a particularly complex process involving several regions of viral surface GPs. Our results suggest that for HBV, this mechanism could be triggered by ERp57, allowing a thiol/disulfide exchange reaction to occur and regulate isomerization of critical CSD(s), which ultimately results in the exposition of the fusion peptide that seems to be located within the preS1 region.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for figures 1-3, 5-7 and 9.

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Author details

1. Jimena Pérez-Vargas

   CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Elin Teppa

   Competing interests

   No competing interests declared

2. Elin Teppa

   1. Sorbonne Université, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, Paris, France
   2. Sorbonne Université, Institut des Sciences du Calcul et des Données (ISCD), Paris, France

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Jimena Pérez-Vargas

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0691-9654

3. Fouzia Amirache

   CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6453-3717

4. Bertrand Boson

   CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1920-5172

5. Rémi Pereira de Oliveira

   CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3005-1277

6. Christophe Combet

   Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 - CNRS 5286 - Université Lyon 1 - Centre Léon Bérard, Lyon, France

   Contribution

   Resources, Software

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7348-3520

7. Anja Böckmann

   Molecular Microbiology and Structural Biochemistry, UMR5086 CNRS-Université Lyon 1, Lyon, France

   Contribution

   Resources, Software

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8149-7941

8. Floriane Fusil

   CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

9. Natalia Freitas

   CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing - review and editing

   Contributed equally with

   Alessandra Carbone and François-Loïc Cosset

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8821-561X

10. Alessandra Carbone

    Sorbonne Université, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, Paris, France

    Contribution

    Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Visualization, Methodology, Writing - original draft

    Contributed equally with

    Natalia Freitas and François-Loïc Cosset

    For correspondence

    Alessandra.Carbone@lip6.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-2098-5743

11. François-Loïc Cosset

    CIRI – Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, Lyon, France

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Visualization, Writing - original draft, Project administration, Writing - review and editing

    Contributed equally with

    Natalia Freitas and Alessandra Carbone

    For correspondence

    Francois-Loic.Cosset@ens-lyon.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-8842-3726

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