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Humberto J. Debat - One of the best experts on this subject based on the ideXlab platform.
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Complete genome sequence of a divergent strain of Tibetan frog hepatitis B virus associated with a concave-eared torrent frog (Odorrana tormota)
Archives of Virology, 2019Co-Authors: Humberto J. DebatAbstract:Viruses of the family Hepadnaviridae are characterized by partially dsDNA circular genomes of approximately 3.2 kb, which are reverse transcribed from RNA intermediates. Hepadnaviruses have a broad host range, which includes humans (hepatitis B virus), other mammals (genus Orthohepadnavirus ), and birds (genus Avihepadnavirus ). The known host specificity of hepadnaviruses has been expanded by reports of new viruses infecting fish, amphibians, and reptiles. Tibetan frog hepatitis B virus (TFHBV) was recently discovered in a member of the species Nanorana parkeri (family Dicroglossidae) from Tibet. To increase our understanding of hepadnaviruses that infect amphibian hosts, we identified the full-length genome of a divergent strain, TFHBV-Ot, associated with a concave-eared torrent frog ( Odorrana tormota , family Ranidae) from China by searching deep-sequencing data. TFHBV-Ot shared a genomic organization and 76.6% overall genome sequence nucleotide identity with the prototype TFHBV associated with N. parkeri (TFHBV-Np). The pairwise amino acid sequence identity between the predicted gene products of TFHBV-Ot and TFHBV-Np ranged between 63.9% and 77.9%. Multiple tissue/organ-specific RNAseq datasets suggested a broad tropism of TFHBV, including muscle, gonads and brain. In addition, we provide information about putative virus-derived small RNAs from an amphibian hepadnavirus. The results presented here expand the known genetic diversity and host range of TFHBV to Ranidae frogs, and warrant an investigation of hepadnaviral infection of amphibian brains.
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Complete genome sequence of a divergent strain of Tibetan frog hepatitis B virus associated to concave-eared torrent frog Odorrana tormota
2018Co-Authors: Humberto J. DebatAbstract:The family Hepadnaviridae is characterized by partially dsDNA circular viruses of approximately 3.2 kb, which are reverse transcribed from RNA intermediates. Hepadnaviruses (HBVs) have a broad host range which includes humans (Hepatitis B virus), other mammals (genus Orthohepadnavirus), and birds (Avihepadnavirus). HBVs host specificity has been expanded by reports of new viruses infecting fish, amphibians, and reptiles. The tibetan frog hepatitis B virus (TFHBV) was recently discovered in Nanorana parkeri (Family Dicroglossidae) from Tibet. To increase understanding of hepadnavirus in amphibian host, we identified the full-length genome of a divergent strain TFHBV-Ot associated to the concave-eared torrent frog Odorrana tormota (Family Ranidae) from China by searching deep sequencing data. TFHBV-Ot shared the genomic organization and a 76.6% overall genome nucleotide identity to the prototype TFHBV associated to N. parkeri (TFHBV-Np). TFHBV-Ot amino acid pairwise identity with TFHBV-Np predicted gene products ranged between 63.9% and 77.9%. Multiple tissue/organ specific RNAseq datasets suggest a broad tropism of TFHBV including muscles, gonads and brains. In addition, we provide for the first time evidence of virus derived small RNA from an amphibian hepadnavirus, tentatively enriched in 19-20 nt species and cytidine as first base. The results presented here expand the genetic diversity and the host range of TFHBV to Ranidae frogs, and warrant investigation on hepadnaviral infection of amphibian brains.
David Guillaume - One of the best experts on this subject based on the ideXlab platform.
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Vers des études structurales de particules sous-virales d'Hepadnavirus par expression acellulaire à partir de germes de blé et RMN du solide
HAL CCSD, 2019Co-Authors: David GuillaumeAbstract:Structural studies of eukaryotic membrane proteins are of prime importance but notoriously difficult as they not only necessitate an efficient and practical overexpression system that allows for membrane protein expression in a biologically relevant folding, but also a structural technique that you can easily combine with the chosen protein production system. In vitro cell-free systems, due to their modulable nature, are particularly suited for membrane protein expression. Furthermore, they now established themselves as a viable alternative to conventional cell-based expression, notably because of considerable advances in robustness and efficiency. Amongst them, the wheat germ cell-free production system (WG-CFPS) proved to be the most efficient for production of eukaryotic membrane proteins, and allows for efficient and specific isotope labeling. This makes it particularly convenient for Nuclear Magnetic Resonance (NMR), and more specifically solid-state NMR which is particularly appropriate for membrane protein studies and macromolecular assemblies. Thanks to very recent advances that lead to a drastic reduction of the quantity of protein needed, solid-state NMR is now compatible with WG-CFPS, creating a powerful tool for structural studies of macromolecular assemblies and membrane proteins. In this work, these two techniques are combined for the production and study of the envelope proteins from the duck Hepatitis B Virus (DHBV), that belongs to the Hepadnaviridae family. These viruses are able to secrete active virions, but also particles composed only of envelope proteins, which are called subviral particles (SVPs). In the first part, we show here that the DHBV small envelope protein (DHBs S) is produced as soluble in mg amounts using WG-CFPS. Even more, the protein forms SVPs upon translation, and is thus expressed in a biologically relevant form. After SVPs disassembly, the protein displays a mostly -helical folding, which is characteristic of a well-folded protein, and also very similar to the secondary structure of an assembly-incompetent mutant. After further isolation by ultracentrifugation on a sucrose gradient, the SVPs were sedimented in a 0.7 mm rotor and observed by solid-state NMR. Very promising hNH 2D spectra, with a good signal, were obtained. They display numerous isolated peaks and a resolution alike to other sedimented membrane proteins observed by solid-state NMR. Moreover, superimposition of the DHBs S spectrum with simulated spectra from proteins with extreme secondary structure content confirms that the protein is mostly -helical in the context of the SVPs. Nonetheless, the signal still needs to be improved in order to perform the experiments necessary for in-depth structural analysis. To that end, sample optimization assays were conducted. On the one hand, protein yield improvement, by the use of a commercial wheat germ extract, and SVPs stabilization, by incubation with KSCN, were tried. On the other hand, different methods for SVPs purification were tested, including PEG6000 or ammonium sulfate precipitation, incubation at high temperature, contaminant removal with an ultrafiltration device, affinity or size-exclusion purification as well as tests of particles disassembly, purification followed by SVPs reconstitution in lipids. Finally, amino-acid specific isotopic labeling of DHBs S was evaluated. In the second part, we could show extended possibilities of WG-CFPS through expression of DHBV large envelope protein (DHBs L). In vivo, the protein undergo specific phosphorylation as well as alternative translation, and we could show that it is also the case upon wheat germ cell-free expression. We also tested coexpression of DHBs S, DHBs L and of the DHBV capsid in order to assess the possibility of DHBs L inclusion in SVPs, or even complete virion reconstitution, which could even augment WG-CFPS possibilities. Ultimately, we also detail some critical parameters for SVPs formation in the WG-CFPSLes études structurales des protéines membranaires eucaryotes sont importantes mais particulièrement difficiles à effectuer car elles nécessitent non seulement un système efficace et pratique pour produire la protéine dans une conformation native, d’une technique d’étude structurale compatible avec ce dernier. Du fait de leur modularité, les systèmes de production acellulaires in vitro sont adaptés à la production de protéines membranaires. De plus, l’amélioration de leur robustesse et de leur efficacité les rendent maintenant comme une alternative viable à l’expression cellulaire. Parmi ceux-ci, le Système d’Expression Acellulaire à partir de Germes de Blé (SEA-GB) est le plus efficace pour produire des protéines membranaires eucaryotes, et permet de plus un marquage isotopique efficace et spécifique. Ce dernier point est très utile pour la Résonance Magnétique Nucléaire (RMN), et plus spécifiquement la RMN du solide qui permet l’étude structure de protéines membranaires et d’assemblages macromoléculaires. Depuis récemment, la RMN du solide est compatible avec le SEA-GB, formant un outil puissant pour l’étude structurale de protéines membranaires et assemblages macromoléculaires. Dans ces travaux, les deux techniques ont été combinées pour la production et l’étude des protéines d’enveloppe du virus de l’Hépatite B du canard (VHBC), appartenant à la famille des Hepadnaviridae. Ces virus sont capables de sécréter des virions actifs, mais aussi des particules composées uniquement de protéines d’enveloppe, appelées particules sous-virales (PSV). Dans un premier temps, nous montrons que plusieurs milligrammes de petite protéine d’enveloppe (DHBs S) du VHBC sont produits sous forme soluble avec le SEA-GB. DHBs S forme des PSV durant la traduction, ce qui confirme la conformation native de la protéine. Après désassemblage des PSV, la protéine est majoritairement en hélice , synonyme d’un bon repliement. Après isolation par ultracentrifugation sur gradient de sucrose, les PSV ont été sédimentées dans un rotor de 0.7 mm et étudiées par RMN du solide. Des spectres 2D hNH très prometteurs ont été obtenus, avec un bon signal, des pics isolés et une résolution similaire à celle d’autres protéines membranaires sédimentées et étudiées par RMN du solide. De plus, la superposition du spectre de DHBs S avec des spectres simulés de protéines modèles possédant des structures secondaires caractéristiques confirme que DHBs S est principalement en hélice dans le contexte des PSV. Le signal doit cependant être amélioré pour pouvoir réaliser les expériences nécessaires à des études structurales approfondies, c’est pourquoi des tests d’optimisation de la production ont été effectués. D’une part, l’amélioration du rendement de production, via l’utilisation d’un extrait de germes de blé commercial, et de la stabilisation des PSV, par incubation avec du KSCN, ont été testés. D’autre part, différentes méthodes de purification ont été examinées: précipitation à l’ammonium sulfate ou au PEG6000, incubation à haute température, élimination de contaminants via une unité d’ultrafiltration, purification d’affinité ou d’exclusion stérique ainsi qu’un test de désassemblage des particules, suivie d’une purification puis de la reconstitution des PSVs en présence de lipides. Enfin, un marquage isotopique spécifique de certains acides aminés a été évalué. Dans la seconde partie, nous avons étendu les possibilités du SEA-GB via l’expression de la grande protéine d’enveloppe (DHBs L) du VHBC. In vivo, la protéine est phosphorylée spécifiquement et subit aussi une traduction alternative ; nous avons montré que c’était aussi le cas dans le SEA-GB. Nous avons aussi testé la coexpression de DHBs S, DHBs L ainsi que de la capside de DHBV pour inclure DHBs L dans les PSV, voire même reconstituer des virions entiers, ce qui augmenterait les possibilités du système. Enfin, nous avons aussi détaillé certains paramètres critiques pour la formation des PSV dans le systèm
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Vers des études structurales de particules sous-virales d'Hepadnavirus par expression acellulaire à partir de germes de blé et RMN du solide
2019Co-Authors: David GuillaumeAbstract:Les études structurales des protéines membranaires eucaryotes sont importantes mais particulièrement difficiles à effectuer car elles nécessitent non seulement un système efficace et pratique pour produire la protéine dans une conformation native, d’une technique d’étude structurale compatible avec ce dernier. Du fait de leur modularité, les systèmes de production acellulaires in vitro sont adaptés à la production de protéines membranaires. De plus, l’amélioration de leur robustesse et de leur efficacité les rendent maintenant comme une alternative viable à l’expression cellulaire. Parmi ceux-ci, le Système d’Expression Acellulaire à partir de Germes de Blé (SEA-GB) est le plus efficace pour produire des protéines membranaires eucaryotes, et permet de plus un marquage isotopique efficace et spécifique. Ce dernier point est très utile pour la Résonance Magnétique Nucléaire (RMN), et plus spécifiquement la RMN du solide qui permet l’étude structure de protéines membranaires et d’assemblages macromoléculaires. Depuis récemment, la RMN du solide est compatible avec le SEA-GB, formant un outil puissant pour l’étude structurale de protéines membranaires et assemblages macromoléculaires. Dans ces travaux, les deux techniques ont été combinées pour la production et l’étude des protéines d’enveloppe du virus de l’Hépatite B du canard (VHBC), appartenant à la famille des Hepadnaviridae. Ces virus sont capables de sécréter des virions actifs, mais aussi des particules composées uniquement de protéines d’enveloppe, appelées particules sous-virales (PSV). Dans un premier temps, nous montrons que plusieurs milligrammes de petite protéine d’enveloppe (DHBs S) du VHBC sont produits sous forme soluble avec le SEA-GB. DHBs S forme des PSV durant la traduction, ce qui confirme la conformation native de la protéine. Après désassemblage des PSV, la protéine est majoritairement en hélice , synonyme d’un bon repliement. Après isolation par ultracentrifugation sur gradient de sucrose, les PSV ont été sédimentées dans un rotor de 0.7 mm et étudiées par RMN du solide. Des spectres 2D hNH très prometteurs ont été obtenus, avec un bon signal, des pics isolés et une résolution similaire à celle d’autres protéines membranaires sédimentées et étudiées par RMN du solide. De plus, la superposition du spectre de DHBs S avec des spectres simulés de protéines modèles possédant des structures secondaires caractéristiques confirme que DHBs S est principalement en hélice dans le contexte des PSV. Le signal doit cependant être amélioré pour pouvoir réaliser les expériences nécessaires à des études structurales approfondies, c’est pourquoi des tests d’optimisation de la production ont été effectués. D’une part, l’amélioration du rendement de production, via l’utilisation d’un extrait de germes de blé commercial, et de la stabilisation des PSV, par incubation avec du KSCN, ont été testés. D’autre part, différentes méthodes de purification ont été examinées: précipitation à l’ammonium sulfate ou au PEG6000, incubation à haute température, élimination de contaminants via une unité d’ultrafiltration, purification d’affinité ou d’exclusion stérique ainsi qu’un test de désassemblage des particules, suivie d’une purification puis de la reconstitution des PSVs en présence de lipides. Enfin, un marquage isotopique spécifique de certains acides aminés a été évalué. Dans la seconde partie, nous avons étendu les possibilités du SEA-GB via l’expression de la grande protéine d’enveloppe (DHBs L) du VHBC. In vivo, la protéine est phosphorylée spécifiquement et subit aussi une traduction alternative ; nous avons montré que c’était aussi le cas dans le SEA-GB. Nous avons aussi testé la coexpression de DHBs S, DHBs L ainsi que de la capside de DHBV pour inclure DHBs L dans les PSV, voire même reconstituer des virions entiers, ce qui augmenterait les possibilités du système. Enfin, nous avons aussi détaillé certains paramètres critiques pour la formation des PSV dans le systèmeStructural studies of eukaryotic membrane proteins are of prime importance but notoriously difficult as they not only necessitate an efficient and practical overexpression system that allows for membrane protein expression in a biologically relevant folding, but also a structural technique that you can easily combine with the chosen protein production system. In vitro cell-free systems, due to their modulable nature, are particularly suited for membrane protein expression. Furthermore, they now established themselves as a viable alternative to conventional cell-based expression, notably because of considerable advances in robustness and efficiency. Amongst them, the wheat germ cell-free production system (WG-CFPS) proved to be the most efficient for production of eukaryotic membrane proteins, and allows for efficient and specific isotope labeling. This makes it particularly convenient for Nuclear Magnetic Resonance (NMR), and more specifically solid-state NMR which is particularly appropriate for membrane protein studies and macromolecular assemblies. Thanks to very recent advances that lead to a drastic reduction of the quantity of protein needed, solid-state NMR is now compatible with WG-CFPS, creating a powerful tool for structural studies of macromolecular assemblies and membrane proteins. In this work, these two techniques are combined for the production and study of the envelope proteins from the duck Hepatitis B Virus (DHBV), that belongs to the Hepadnaviridae family. These viruses are able to secrete active virions, but also particles composed only of envelope proteins, which are called subviral particles (SVPs). In the first part, we show here that the DHBV small envelope protein (DHBs S) is produced as soluble in mg amounts using WG-CFPS. Even more, the protein forms SVPs upon translation, and is thus expressed in a biologically relevant form. After SVPs disassembly, the protein displays a mostly -helical folding, which is characteristic of a well-folded protein, and also very similar to the secondary structure of an assembly-incompetent mutant. After further isolation by ultracentrifugation on a sucrose gradient, the SVPs were sedimented in a 0.7 mm rotor and observed by solid-state NMR. Very promising hNH 2D spectra, with a good signal, were obtained. They display numerous isolated peaks and a resolution alike to other sedimented membrane proteins observed by solid-state NMR. Moreover, superimposition of the DHBs S spectrum with simulated spectra from proteins with extreme secondary structure content confirms that the protein is mostly -helical in the context of the SVPs. Nonetheless, the signal still needs to be improved in order to perform the experiments necessary for in-depth structural analysis. To that end, sample optimization assays were conducted. On the one hand, protein yield improvement, by the use of a commercial wheat germ extract, and SVPs stabilization, by incubation with KSCN, were tried. On the other hand, different methods for SVPs purification were tested, including PEG6000 or ammonium sulfate precipitation, incubation at high temperature, contaminant removal with an ultrafiltration device, affinity or size-exclusion purification as well as tests of particles disassembly, purification followed by SVPs reconstitution in lipids. Finally, amino-acid specific isotopic labeling of DHBs S was evaluated. In the second part, we could show extended possibilities of WG-CFPS through expression of DHBV large envelope protein (DHBs L). In vivo, the protein undergo specific phosphorylation as well as alternative translation, and we could show that it is also the case upon wheat germ cell-free expression. We also tested coexpression of DHBs S, DHBs L and of the DHBV capsid in order to assess the possibility of DHBs L inclusion in SVPs, or even complete virion reconstitution, which could even augment WG-CFPS possibilities. Ultimately, we also detail some critical parameters for SVPs formation in the WG-CFP
Junqi Niu - One of the best experts on this subject based on the ideXlab platform.
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identification of bst 2 tetherin induced hepatitis b virus restriction and hepatocyte specific bst 2 inactivation
Scientific Reports, 2015Co-Authors: Biao Zhang, Ying Shi, Zhu Han, Yan Zhang, Yulai Zhou, Wenyan Zhang, Junqi NiuAbstract:BST-2/tetherin is an interferon-inducible antiviral protein that blocks the release of various enveloped viruses, including HIV-1. Hepatitis B virus (HBV), a major cause of liver disease, belongs to the Hepadnaviridae family of enveloped DNA viruses. Whether BST-2 regulates HBV production is largely unknown. In this report, we have demonstrated that HBV particle release is modulated by BST-2 in a cell type-dependent fashion. In HEK293T cells, ectopically expressed or interferon-induced BST-2 strongly inhibited HBV release. BST-2 co-localized with HBV surface protein at multivesicular bodies (MVBs) and physically interacted with HBV particles. However, exogenous BST-2-induced HBV restriction was weak in Huh-7 hepatoma cells, and the interferon-induced anti-HBV effect was independent of BST-2 induction in hepatic L02 cells. Notably, HBV could promote HIV-1 ΔVpu virus release from BST-2-positive HepG2 hepatoma cells but not HeLa cells, whereas Vpu failed to efficiently inhibit BST-2-induced HBV restriction. HBx exhibited an enhanced interaction and co-localization with BST-2 in hepatocytes. These observations indicate that BST-2 restricts HBV production at intracellular MVBs but is inactivated by HBV through a novel mechanism requiring hepatocyte-specific cellular co-factors or a hepatocyte-specific environment. Further understanding of BST-2-induced HBV restriction may provide new therapeutic targets for future HBV treatments.
Lucie Etienne - One of the best experts on this subject based on the ideXlab platform.
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smc5 6 antagonism by hbx is an evolutionarily conserved function of hepatitis b virus infection in mammals
Journal of Virology, 2018Co-Authors: Fabien Abdul, Fabien Filleton, Laetitia Gerossier, Alexia Paturel, Janet E Hall, Michel Strubin, Lucie EtienneAbstract:Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family Hepadnaviridae) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has, however, evolved to counteract this defense mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionarily conserved function is unknown. In this study, we used an evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the Smc5/6 complex subunits and found that they have been conserved in primates and mammals. Yet, Smc6 showed marks of adaptive evolution, potentially reminiscent of a virus-host "arms race." We then functionally tested the HBx proteins from six divergent hepadnaviruses naturally infecting primates, rodents, and bats. We demonstrate that despite little sequence homology, these HBx proteins efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all HBx proteins also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionarily conserved requirement for Smc5/6 inactivation by HBx, showing that Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. It will be interesting to investigate whether Smc5/6 may further be a restriction factor of other, yet-unidentified viruses that may have driven some of its adaptation.IMPORTANCE Infection with hepatitis B virus (HBV) led to 887,000 human deaths in 2015. HBV has been coevolving with mammals for millions of years. Recently, the Smc5/6 complex, which has essential housekeeping functions, was identified as a restriction factor of human HBV antagonized by the regulatory HBx protein. Here we address whether the antiviral activity of Smc5/6 is an important evolutionarily conserved function. We found that all six subunits of Smc5/6 have been conserved in primates, with only Smc6 showing signatures of an "evolutionary arms race." Using evolution-guided functional analyses that included infections of primary human hepatocytes, we demonstrated that HBx proteins from very divergent mammalian HBVs could all efficiently antagonize Smc5/6, independently of the host species and sites under positive selection. These findings show that Smc5/6 antiviral activity against HBV is an important function in mammals. They also raise the intriguing possibility that Smc5/6 may restrict other, yet-unidentified viruses.
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smc5 6 antagonism by hbx is an evolutionary conserved function of hepatitis b virus infection in mammals
bioRxiv, 2017Co-Authors: Fabien Filleton, Fabien Abdul, Laetitia Gerossier, Alexia Paturel, Janet E Hall, Michel Strubin, Lucie EtienneAbstract:Infection with Hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. HBVs (family Hepadnaviridae) have been associated with mammals for millions of years. Recently, the Smc5/6 complex, known for its essential housekeeping functions in genome maintenance, was identified as an antiviral restriction factor of human HBV. The virus has however developed a counteraction mechanism by degrading the complex via its regulatory HBx protein. Whether the antiviral activity of the Smc5/6 complex against hepadnaviruses is an important and evolutionary-conserved function is unknown. Here, we used a combined evolutionary and functional approach to address this question. We first performed phylogenetic and positive selection analyses of the six Smc5/6 complex subunits and found that they have been highly conserved in primates and mammals. Yet, the Smc6 subunit showed marks of adaptive evolution, potentially reminiscent of virus-host 9arms-race9. We then functionally tested the HBx from six very divergent hepadnaviruses now naturally infecting primates, rodents, and bats. Despite little sequence homology, we demonstrate that these HBx efficiently degraded mammalian Smc5/6 complexes, independently of the host species and of the sites under positive selection. Importantly, all also rescued the replication of an HBx-deficient HBV in primary human hepatocytes. These findings point to an evolutionary-conserved requirement for Smc5/6 inactivation by HBx, showing that the Smc5/6 antiviral activity has been an important defense mechanism against hepadnaviruses in mammals. Interestingly, Smc5/6 may further be a restriction factor of other yet unidentified viruses that have driven some of its adaptation.
Biao Zhang - One of the best experts on this subject based on the ideXlab platform.
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identification of bst 2 tetherin induced hepatitis b virus restriction and hepatocyte specific bst 2 inactivation
Scientific Reports, 2015Co-Authors: Biao Zhang, Ying Shi, Zhu Han, Yan Zhang, Yulai Zhou, Wenyan Zhang, Junqi NiuAbstract:BST-2/tetherin is an interferon-inducible antiviral protein that blocks the release of various enveloped viruses, including HIV-1. Hepatitis B virus (HBV), a major cause of liver disease, belongs to the Hepadnaviridae family of enveloped DNA viruses. Whether BST-2 regulates HBV production is largely unknown. In this report, we have demonstrated that HBV particle release is modulated by BST-2 in a cell type-dependent fashion. In HEK293T cells, ectopically expressed or interferon-induced BST-2 strongly inhibited HBV release. BST-2 co-localized with HBV surface protein at multivesicular bodies (MVBs) and physically interacted with HBV particles. However, exogenous BST-2-induced HBV restriction was weak in Huh-7 hepatoma cells, and the interferon-induced anti-HBV effect was independent of BST-2 induction in hepatic L02 cells. Notably, HBV could promote HIV-1 ΔVpu virus release from BST-2-positive HepG2 hepatoma cells but not HeLa cells, whereas Vpu failed to efficiently inhibit BST-2-induced HBV restriction. HBx exhibited an enhanced interaction and co-localization with BST-2 in hepatocytes. These observations indicate that BST-2 restricts HBV production at intracellular MVBs but is inactivated by HBV through a novel mechanism requiring hepatocyte-specific cellular co-factors or a hepatocyte-specific environment. Further understanding of BST-2-induced HBV restriction may provide new therapeutic targets for future HBV treatments.