Approches ”perte de fonction” pour l'étude des interactions ...

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HAL Id: tel-03543191 https://tel.archives-ouvertes.fr/tel-03543191 Submitted on 25 Jan 2022 HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Approches ”perte de fonction” pour l’étude des interactions hôte-virus dans le cas des hépatites virales chroniques Vincent Turon-Lagot To cite this version: Vincent Turon-Lagot. Approches ”perte de fonction” pour l’étude des interactions hôte-virus dans le cas des hépatites virales chroniques. Virologie. Université de Strasbourg, 2020. Français. NNT: 2020STRAJ068. tel-03543191

Transcript of Approches ”perte de fonction” pour l'étude des interactions ...

HAL Id: tel-03543191https://tel.archives-ouvertes.fr/tel-03543191

Submitted on 25 Jan 2022

HAL is a multi-disciplinary open accessarchive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come fromteaching and research institutions in France orabroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, estdestinée au dépôt et à la diffusion de documentsscientifiques de niveau recherche, publiés ou non,émanant des établissements d’enseignement et derecherche français ou étrangers, des laboratoirespublics ou privés.

Approches ”perte de fonction” pour l’étude desinteractions hôte-virus dans le cas des hépatites virales

chroniquesVincent Turon-Lagot

To cite this version:Vincent Turon-Lagot. Approches ”perte de fonction” pour l’étude des interactions hôte-virus dansle cas des hépatites virales chroniques. Virologie. Université de Strasbourg, 2020. Français. �NNT :2020STRAJ068�. �tel-03543191�

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Hepatitis B Virus Evasion From CyclicGuanosine Monophosphate–AdenosineMonophosphate Synthase Sensingin Human HepatocytesEloi R. Verrier,1* Seung-Ae Yim,1* Laura Heydmann,1 Houssein El Saghire,1 Charlotte Bach,1 Vincent Turon-Lagot,1

Laurent Mailly,1 Sarah C. Durand,1 Julie Lucifora,2 David Durantel,2 Patrick Pessaux,1,3 Nicolas Manel,4,5 Ivan Hirsch,6

Mirjam B. Zeisel,1 Nathalie Pochet,7 Catherine Schuster,1* and Thomas F. Baumert1,3*

Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mecha-

nisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood.

Recently, the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) was identified as a DNA sen-

sor. In this study, we investigated the functional role of cGAS in sensing HBV infection and elucidate the mechanisms of

viral evasion. We performed functional studies including loss-of-function and gain-of-function experiments combined with

cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes, and HBV-

infected human liver chimeric mice. Here, we show that cGAS is expressed in the human liver, primary human hepato-

cytes, and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner

in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during

HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the

hepatocyte cGAS pathway is functionally active, as shown by reduction of viral covalently closed circular DNA levels in

gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized

mice. Conclusion: HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector path-

ways. (HEPATOLOGY 2018; 68:1695-1709).

With more than 250 million chronicallyinfected patients, hepatitis B virus (HBV)infection is a leading cause of liver disease

and hepatocellular carcinoma.(1,2) Current antiviraltherapies effectively control viral load but largely fail tocure.(3) HBV is a partially double-stranded DNA(dsDNA) virus infecting human hepatocytes after ini-tial attachment to heparan sulfate proteoglycans and its

receptor Na1/taurocholate cotransporting polypeptide(NTCP; reviewed in Verrier et al.(4)). Followinguncoating, the viral nucleocapsid is released into thecytoplasm. The viral genome is imported into thenucleus through mechanisms which are still poorlyunderstood. The viral genome is converted in the nu-cleus into a covalently closed circular DNA (cccDNA).(5) This minichromosome serves as a template

Abbreviations: Cas9, CRISPR-associated 9; cccDNA, covalently closed circular DNA; cDNA, complementary DNA; cGAMP, cyclic guanosine mono-phosphate–adenosine monophosphate; cGAS, cyclic guanosine monophosphate–adenosine monophosphate synthase; CRISPR, clustered regularly interspacedshort palindromic repeats; DIG, digoxigenin; dsDNA, double-stranded DNA; FDR, false discovery rate; FISH, fluorescence in situ hybridization;GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GSEA, gene set enrichment analysis; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus;HIV, human immunodeficiency virus; IAR, innate antiviral response gene set; IFI16, IFN-c-inducible protein 16; IFN, interferon; IFNB1, IFN beta1; IFNL1, IFN lambda 1; ISG, IFN-stimulated gene; KO, knockout; MB21D1, Mab-21 domain-containing protein 1; MOI, multiplicity of infec-tion; NTCP, Na1/taurocholate cotransporting polypeptide; ORF, open reading frame; PEG, polyethylene glycol; pgRNA, pregenomic RNA; PHH, pri-mary human hepatocyte; poly(I:C), polyinosinic:polycytidylic acid; rcDNA, relaxed circular DNA; SeV, Sendai virus; sgRNA, single-guide RNA;siRNA, small interfering RNA; STING, stimulator of IFN genes; TBK1, TANK binding kinase 1; TMEM173, transmembrane protein 173; uPA/SCID-bg, urokinase-type plasminogen activator/severe combined immunodeficient beige.

Received December 14, 2017; accepted April 18, 2018.

Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.30054/suppinfo.

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for both pregenomic RNA (pgRNA) and viral mRNAtranscription. While recent studies have suggestedsensing of the pgRNA or other HBV RNAs by eitherMDA5(6) or RIG-I,(7) the recognition of the viralnucleic acids by the regular pattern recognition recep-tors remains elusive. In general, HBV does not or doesonly marginally activate innate immune responses incell culture models and in vivo,(8-14) leading to theconcept that HBV behaves like a “stealth” virus avoid-ing viral DNA and RNA sensing.(15) Other studieshave suggested an active inhibition of the innateimmune responses by HBV proteins.(16) Consequently,the interaction of HBV and the innate immune systemof hepatocytes, and in particular the sensing of HBVDNA, is only poorly understood.Foreign DNA recognition by cytosolic DNA sensors

triggers an early antiviral innate immune response,including type I and type III interferon (IFN) produc-tion.(17) Recently, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS)was identified as a DNA sensor exhibiting antiviralactivity against a broad range of DNA and RNAviruses.(18-20) cGAS is encoded by the Mab-21 domain-

containing protein 1 (MB21D1) gene and directly bindsto dsDNAs, inducing the production of cGAMP,which is recognized by the stimulator of IFN genes(STING, encoded by transmembrane protein 173[TMEM173]), triggering the expression of IFN-stimulated genes (ISGs) through TANK binding kinase1 (TBK1) activation.(21-23) While two studies haveinvestigated cGAS–HBV interactions in viral replica-tion and assembly,(24,25) the functional role of cGAS insensing of the viral genome during natural infection ofhuman hepatocytes remains unknown.The understanding of HBV–host interactions, in-

cluding the innate immune response after infection, hasbeen hampered for a long time by the absence of arobust cell culture model system for the study of viralinfection.(26) The development of HBV-susceptibleNTCP-overexpressing hepatoma cells, such as HepG2-NTCP cells, allows the study of the full life cycle in arobust and easy-to-use cell culture model.(26) HepG2cells are capable of mounting an efficient innate im-mune response after infection by hepatitis C virus.(27)

Moreover, another study took advantage of HBV-infected HepG2-NTCP for studying the interaction

*These authors contributed equally to this work, as first authors.**These authors contributed equally to this work, as senior authorsSupported by the European Union (ERC-AdG-2014-671231-HEPCIR, EU H2020-667273-HEPCAR, EU-InfectEra HepBccc), the National Insti-

tutes of Health (National Institute of Allergy and Infectious Diseases, 1R03AI131066-01A1 and U19AI123862; National Cancer Institute, R21CA209940), the Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS, 2015/1099), the Fondation ARC pour la Recherche sur le

Cancer (TheraHCC IHUARC IHU201301187, GACR 17-15422S), and a PhD fellowship of the R�egion Alsace, France. The work has been publishedunder the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National ResearchAgency as part of the Investments for the Future program. E.R.V. was supported by a fellowship from the ANRS (ECTZ50121).

VC 2018 by the American Association for the Study of Liver Diseases.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.30054

Potential conflict of interest: Dr. Pessaux consults for Integra and Merck. He owns stock in Virtualisure.

ARTICLE INFORMATION:

From the 1Universit�e de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et H�epatiques UMRS_1110, Strasbourg,France; 2Inserm, U1052, Cancer Research Center of Lyon (CRCL), Universit�e de Lyon (UCBL1), CNRS UMR_5286, Centre L�eonB�erard, Lyon, France; 3Pole H�epato-Digestif, Institut Hospitalo-Universitaire, Hopitaux Universitaires de Strasbourg, Strasbourg, France;4Immunity and Cancer Department, Institut Curie, PSL Research University, Paris, France; 5Inserm, U932, Paris, France; 6Department ofGenetics and Microbiology, Faculty of Science, Biocev, Charles University; Institute of Organic Chemistry and Biochemistry, CAS, IOCB& Gilead Research Center, Prague, Czech Republic; 7Ann Romney Center for Neurologic Diseases, Department of Neurology, Brighamand Women’s Hospital, Harvard Medical School, Boston, MA; Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge,MA.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:

Thomas F. Baumert, M.D., Catherine Schuster, Ph.D.,or Eloi R. Verrier, Ph.D.Inserm UMRS_1110, Institut de Recherche sur les Maladies Virales etH�epatiques3 Rue Koeberl�e

67000 Strasbourg, FranceE-mail: [email protected],[email protected], or [email protected]: 133-3-68-85-37-03

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between RIG-I and HBV RNA,(7) suggesting that thiscell line is suitable for the study of the innate immuneresponse after HBV infection. Here, we aimed tounderstand the functional role of cGAS for the HBVlife cycle in human hepatocytes and unravel the mecha-nisms of viral evasion using loss-of-function and gain-of-function experiments combined with cGAS effectorgene expression profiling in human liver chimeric mice.

Patients and Methods

HUMAN SUBJECTS

Human material including liver tissue from patientsundergoing surgical resection or HBV-positive serumwas obtained with informed consent from all patients.Protocols were approved by the Ethics Committee ofthe University of Strasbourg Hospitals, France (CPP10-17 and DC-2016-2616).

ANIMAL EXPERIMENTATION

All mice were kept in a specific pathogen-free ani-mal housing facility at Inserm UMRS_1110. Therespective protocols were approved by the Ethics Com-mittee of the University of Strasbourg Hospitals andauthorized by the French Ministry of Research (nos.02014120416254981AL/02/19/08/12, AL/01/18/08/1202014120416254981, 0201412051105 4408). Micewere kept in individual ventilated cages, with beddingcomposed of irradiated sawdust and chips from spruceand pine and enriched with cotton cocoon and aspenbricks. The animal diet consisted of 25 kGy irradiatedRM3(E) (SDS) and mice were not fasted. Primaryhuman hepatocytes (PHHs) were transplanted into 3-week-old urokinase-type plasminogen activator/severecombined immunodeficient beige (uPA/SCID-bg)mice (male and female) by intrasplenic injection asdescribed.(28) Engraftment and viability of PHHs wereassessed by quantification of human serum albumin byenzyme-linked immunosorbent assay (E80-129;Bethyl Laboratories).(28) uPA/SCID-bg mice werethen infected with serum-derived HBV and sacrificed16 weeks after virus inoculation. Serum HBV load wasdetermined by quantitative PCR (Realtime HBV viralload kit; Abbott) before sacrifice. Interventions were allperformed during light cycle.

CELL LINES AND HUMANHEPATOCYTES

HEK 293T(29) and HepG2-NTCP(30) cells as wellas isolation of PHHs have been described.(29)

REAGENTS AND PLASMIDS

Dimethyl sulfoxide (DMSO), PEG 8000 (polyeth-ylene glycol), polyinosinic:polycytidylic acid (poly[I:C]), and calf thymus DNA (control dsDNA) wereobtained from Sigma-Aldrich; pReceiver-Lv151 plas-mid was from GeneCopoeia; and lentiCas9-Blast andlentiGuide-Puro plasmids were gifts from Feng Zhang(Addgene 52962 and 52963).

SMALL INTERFERING RNAsFOR FUNCTIONAL STUDIES

Pools of ON-TARGET plus (Dharmacon) smallinterfering RNA (siRNA) targeting MB21D1(cGAS), TMEM173 (STING), TBK1, and IFN-c-inducible protein 16 (IFI16) expression were reverse-transfected into HepG2-NTCP using LipofectamineRNAi-MAX (Invitrogen) as described.(29) RNA waspurified from cells harvested 2 days after transfection,and gene expression was analyzed using quantitativeRT-PCR.

HepG2-NTCP-cGASOVEREXPRESSING AND MB21D1

KNOCKOUT CELLS

Lentivirus particles were generated in HEK 293Tcells by cotransfection of plasmids expressing thehuman immunodeficiency virus (HIV) gap-pol, thevesicular stomatitis virus glycoprotein, and either thehuman MB21D1 full open reading frame (ORF)encoding plasmid, the MB21D1-targeting single-guide RNA (sgRNA) encoding plasmids, or the clus-tered regularly interspaced short palindromic repeats(CRISPR)–associated 9 (Cas9) expressing plasmid, ina ratio of 10:3:10. HepG2-NTCP cells were thenplated and transduced with lentivirus encoding eitherthe human MB21D1 ORF or the ORF of the gene forenhanced green fluorescent protein in pReceiver-Lv151 vector (GeneCopoeia) as a control. After 3days, transduced cells were selected with 200 lg/mL ofneomycin (G418). The cGAS-overexpressing andcontrol HepG2-NTCP cells were then further cul-tured in the presence of G418 at 200 lg/mL. For the

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generation of MB21D1 knockout (KO) cell lines, oneMB21D1-targeting sgRNA was designed usingCRISPR Design Tool (Broad Institute, http://www.genome-engineering.org/). The sgRNA sequence tar-geting exon 1 of MB21D1 (sgcGAS 50-CACCGCGGCCCCCATTCTCGTACGG-30) was insertedinto lentiGuide-Puro plasmid.(31) We first generatedCas9-expressing HepG2-NTCP cells after transduc-tion of cells with the lentiCas9-Blast plasmid.(31) Cellswere then selected with 6 lg/mL blasticidin for 10days. HepG2-NTCP-Cas9 cells were seeded in six-well plates at 50% confluence 24 hours prior to trans-duction with the sgcGAS-encoding plasmid. Subpo-pulations of cells were selected from the wholepopulation and cultured independently. cGAS expres-sion was controlled by western blot. Finally, twocGAS-KO cell lines (cGAS_KO#1 and cGAS_KO#2) were selected.

ANALYSIS OF GENEEXPRESSION USINGQUANTITATIVE RT-PCR

Total RNA was extracted using ReliaPrep RNAMiniprep Systems (Promega) and reverse-transcribedinto complementary DNA (cDNA) using the MaximaFirst Strand cDNA Synthesis Kit (Thermo Scientific)according to the manufacturer’s instructions. Geneexpression was then quantified by quantitative PCRusing a CFX96 thermocycler (Bio-Rad). Primers andTaqMan probes for MB21D1 (cGAS), TMEM173(STING), TBK1, IFI16, IFN beta 1 (IFNB1), IFNlambda 1 (IFNL1), and glyceraldehyde 3-phosphatedehydrogenase (GAPDH) mRNA detection wereobtained from ThermoFisher (TaqMan Gene Expres-sion Assay; Applied Biosystems). All values were nor-malized to GAPDH expression.

PROTEIN EXPRESSION

The expression of cGAS, STING, and b-actin pro-teins was assessed by western blot as described(30) usingtwo polyclonal rabbit anti-cGAS antibodies(HPA031700, Sigma, and NBP1-86761, Novus Bio-logicals; see Supporting Information), a polyclonal rab-bit anti-STING antibody (19851-1-AP; Proteintech),and a monoclonal anti-b-actin antibody (mAb-cam8226; Abcam). Protein expression was quantifiedusing ImageJ software.

INFECTION OF HepG2-NTCPCELLS AND PHHs

The purification of infectious recombinant HBVparticles from HepAD38 cells and infection of HepG2-NTCP cells have been described.(30) Briefly,HepG2-NTCP and derived cells were plated 1 dayprior to incubation with HBV in the presence of 4%PEG at a multiplicity of infection (MOI) of �500GEq/cell except where otherwise stated. Sixteen hoursafter HBV inoculation, cells were washed withphosphate-buffered saline and then cultured in 3.5%DMSO primary hepatocyte maintenance medium for10 days. HBV infection was assessed by quantificationof HBV pgRNA using quantitative RT-PCR or HBVtotal DNA using quantitative PCR as described(30) orby immunofluorescence using anti–hepatitis B surfaceantigen (HBsAg) antibody (1044/329; Bio-Techne)and AF647-labeled goat antibody targeting mouseimmunoglobulin Gs (115-605-003; Jackson Research)as described.(30) Southern blot detection of HBVcccDNA was performed using digoxigenin (DIG)-labeled (Roche) specific probes as described.(32) TotalDNA from HBV-infected cells was extracted usingthe Hirt method as described.(33) Specific DIG-labeledprobes for the detection of HBV and mitochondrialDNAs were synthetized using the PCR DIG ProbeSynthesis Kit (Roche) and the primers indicated inSupporting Table S1. PHHs were plated 1 day prior toincubation with a HBV preS1 or a control peptide for1 hour at 378C as described.(30) PHHs were theninfected with recombinant HBV particles for 10 days.HBV infection was assessed by quantification of HBVpgRNA using quantitative RT-PCR and immunofluo-rescence as described above.

SENDAI VIRUS INFECTION

HepG2-NTCP cells and PHHs were infected withSendai virus (SeV) DI-H4 at an MOI of 10 asdescribed.(13)

EXTRACTION OF HBV RELAXEDCIRCULAR DNA FROM HBVINFECTIOUS PARTICLES

HBV relaxed circular DNA (rcDNA) was extractedfrom HBV preparations using the QiaAMP DNAMiniKit protocol (Qiagen). PEG-precipitated cellsupernatants from naive HepG2-NTCP cells wereused as nonvirion controls. The presence of HBV

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DNA was confirmed by PCR and quantified by quan-titative PCR as described(30) (see Supporting Informa-tion). One microgram of rcDNA or dsDNA (calfthymus DNA) was transfected in cells using Lipofect-amine 2000 (Invitrogen) and the CalPhos MammalianTransfection Kit (Clontech) according to the manufac-turers’ instructions. Cells transfected with HepG2-NTCP control supernatants were used as a control.Three days after transfection, total RNA was extractedand purified as described above.

TRANSCRIPTOMIC ANALYSIS BYDIGITAL MULTIPLEXED GENEPROFILING USING nCOUNTERNanoString

Transcriptomic analyses using nCounter Nano-String were performed according to the manufacturer’sinstructions. Specific probes for a set of 36 innate anti-viral response-related (IAR) genes (according toSchoggins et al.(20) and additional genes listed in Sup-porting Table S2) were obtained from the manufac-turer. HepG2-NTCP cells, HepG2-NTCP-derivedcell lines, and PHHs either were infected with HBVor SeV or were transfected with poly(I:C) (100 ng)for 2 days. Alternatively, HepG2-NTCP-Cas9 andHepG2-NTCP-KO_cGAS#2 cells were transfectedwith rcDNA (1 lg) or dsDNA (calf thymus DNA, 1lg) for 3 days. Total RNA was then extracted and sub-jected to the nCounter Digital Analyzer system(NanoString). Alternatively, total liver RNA wasextracted from HBV-infected mice, and gene expres-sion was assessed by either quantitative RT-PCR(MB21D1 expression) or the nCounter Digital Ana-lyzer system. The 36 genes were considered to be anartificial gene set, the IAR gene set. Its perturbation byinfection, transfection, or gain-of-function/loss-of-function studies was assessed through gene set enrich-ment analysis (GSEA).(34) GSEA determines whetheran a priori defined set of genes shows statistically sig-nificant differences between two biological states. Afalse discovery rate (FDR) < 0.05 was considered sta-tistically significant. Heatmaps illustrating the induc-tion (red) or repression (blue) of the genes of the IARcompared to control were illustrated using Morpheussoftware (Broad Institute of MIT and Harvard,Cambridge, MA). Heatmaps illustrating the induction(red) or repression (blue) of individual genes in chime-ric mouse livers were designed using GenePattern(Broad Institute of MIT and Harvard).

FLUORESCENCE IN SITU

HYBRIDIZATION ANALYSES

Fluorescence in situ hybridization (FISH) analyseswere performed as described.(28,35) Briefly, liver sam-ples were collected from mice and then immediatelyembedded into optimal cutting temperature compound(OCT). OCT-embedded liver sections were cryosec-tioned (10 lm) using a cryostat (Leica). Upon fixationwith 4% formaldehyde at 48C, washing, and dehydra-tion in ethanol, tissue sections were boiled at 908C-958C for 1 minute in a pretreatment solution (Affyme-trix-Panomics), followed by a 10-minute digestion inprotease QF (Affymetrix-Panomics) at 408C. Sectionswere then hybridized using specific probe sets targetingHBV (target region nucleotides 483-1473 of HBV[genotype D, GenBank V01460]) and human MD21D1 (VA1-3013492-VC; Affymetrix-Panomics). Pre-amplification, amplification, and detection of boundprobes were performed according to the manufacturer’sinstructions. Finally, pictures were acquired by confo-cal laser scanning microscopy (LSM710; Carl ZeissMicroscopy) and Zen2 software.

STATISTICAL ANALYSIS

Except where otherwise stated, cell culture experi-ments were performed at least 3 times in an indepen-dent manner. Statistical comparisons of the sampleswere performed using a two-tailed Mann-Whitney Utest. For in vivo experiments, a two-tailed unpairedStudent t test was performed for comparing geneexpression from noninfected and HBV-infected mice.*P < 0.05, **P < 0.01, and ***P < 0.001 were consid-ered significant. Significant P values are indicated byasterisks in the figures. Each digital multiplexed geneprofiling experiment was performed using three bio-logical replicates per condition, and the induction orrepression of the gene set was analyzed using GSEA.FDR < 0.05 was considered statistically significant.

Results

EXPRESSION OF cGAS IN PHHsAND AN INFECTIOUS HBV CELLCULTURE MODEL

Prior to its functional characterization, we studiedcGAS/MB21D1 expression in primary hepatocytesand HBV permissive cell lines. cGAS protein expres-sion was easily detectable in PHHs from three

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independent donors (Fig. 1A). Because HBV infectionof primary cells is highly variable and does notallow robust perturbation studies, we used an HBVinfectious cell culture model based on differentiatedhepatocyte-derived HepG2 cells overexpressingNTCP(30)—a key HBV entry factor. cGAS protein isexpressed in HepG2-NTCP cells (Fig. 1A). We vali-dated the specificity of cGAS detection using ansiRNA specifically targeting the MD21B1 expression(sicGAS) and western blots applying two antibodies(Fig. 1A; Supporting Fig. S1). Moreover, we generatedCRISPR-mediated MB21D1 KO cells using a specificsgRNA (Fig. 1B). Two cell lines, KO_cGAS#1 andKO_cGAS#2, were selected for further studies (Fig.1B). Interestingly, the adaptor STING was alsodetected in HepG2-NTCP cells, suggesting a fully

functional cGAS–STING pathway (Fig. 1C). To testthe suitability of these cells as a model to analyzecGAS-mediated innate immune response after virusinfection, we stimulated cells with different analogues ofviral nucleic acids. Stimulation by poly(I:C) or dsDNAtransfection elicited dose-dependent IFNB1 expressionin HepG2-NTCP cells (Fig. 1D). These results suggestthat the cGAS sensing machinery is present and func-tional, even if it is less efficient than the RNA sensingcomplex. Moreover, cGAS protein expression wasinduced by both poly(I:C) and dsDNA stimulation,confirming an efficient IFN response through the up-regulation of ISGs such as MB21D1(36) after RNA orDNA stimulation (Fig. 1E). Collectively, these datashow that the HepG2-NTCP model is suitable to studyinnate immune responses.

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 1. cGAS expression and function in human hepatocytes and in a cell culture model for HBV infection. (A) Detection of endog-enous cGAS protein expression in different cellular models by western blot. Cell lysates from PHHs from 3 independent donors,Huh7.5.1, HepG2, and HepG2-NTCP cells were used. HepG2-NTCP cells were reverse-transfected with siRNA targeting MB21D1(sicGAS) or a nontargeting siRNA control 2 days before cGAS detection. b-actin was used as a western blot control. Individual rep-resentative experiments are shown. (B) Generation of MB21D1 KO cells. MB21D1 KO HepG2-NTCP cell lines were generatedthrough CRISPR/Cas9 technology. The absence or presence of cGAS protein was controlled by western blot using the HPA031700anti-cGAS antibody in Cas9-expressing HepG2-NTCP cells (Cas9) and in different cell lines after transduction with the sgRNA tar-geting MB21D1 (line-A, line-B, line-C, cGAS_KO#1, and cGAS_KO#2). One experiment is shown. (C) Detection of endogenousSTING protein in HepG2-NTCP cells. siRNA targeting TMEM173 (siSTING) or a nontargeting siRNA (siCtrl) was reverse-transfected into HepG2-NTCP cells. Silencing efficacy was assessed by western blot. One experiment is shown. (D,E) Poly(I:C) anddsDNA transfection induce IFNB1 and MB21D1 expression in HepG2-NTCP cells. HepG2-NTCP cells were transfected withincreasing doses of poly(I:C) or calf thymus DNA at the indicated concentrations. IFNB1 mRNA expression was quantified by quan-titative RT-PCR 24 hours after transfection, and cGAS protein expression was assessed by western blot 24 and 48 hours after trans-fection. Quantitative RT-PCR data (D) are expressed as means 6 SD relative to IFNB1 expression (log10) compared tonontransfected control (0, set at 1) from four independent experiments performed in triplicate (dsDNA) or from three independentexperiments performed in triplicate (poly I:C). One representative western blot experiment is shown (E).

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

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HBV EVADES cGAS SENSING

Next, we investigated whether HBV was sensed inHBV permissive cells. To address this question, weinfected HepG2-NTCP cells with recombinant HBV(MOI, 500 GEq/cell) and studied the expression ofIFNB1 at early time points after HBV infection.Because it has been described that HBV infection mayinduce the expression of type III IFN,(7) IFNL1expression was also quantified. The lack of increase inIFNB1 and IFNL1 expression despite efficient infec-tion (Supporting Fig. S2) indicates poor or absentdetection of HBV by cellular sensors (Fig. 2A,B). Incontrast, SeV, known to induce a strong IFN response

in hepatocytes,(13) strongly induced IFNB1 andIFNL1 expression (Fig. 2 A, B). Because cGAS hasbeen shown to induce the expression of a large set ofinnate effector genes (such as OAS2 and IFI44, seeSchoggins et al.(20)), the analysis of expression of a sin-gle effector gene such as IFNB1 may not be sufficientto evaluate cGAS sensing. Therefore, we designed a36 IAR gene set, comprising 29 ISGs whose expres-sion is modulated by cGAS activity described bySchoggins et al.(20) as well as seven established innateimmune response effector genes (Supporting TableS2). We then infected HepG2-NTCP cells with HBVor SeV and measured the innate antiviral immuneresponse at day 2 postinfection by analysis of IAR gene

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 2. Impaired cGAS-mediated sensing of HBV infection in HepG2-NTCP cells. (A,B) HBV infection does not induce IFNB1or IFNL1 expression. HepG2-NTCP cells were infected with HBV (MOI, 500) or SeV (MOI, 10), and total RNA was extractedevery day for 3 days. RNA extracted from naive cells before infection was used as a control (D0). IFNB1 (A) and IFNL1 (B) expres-sion was then assessed by quantitative RT-PCR. Results are expressed as means 6 SD IFNB1/IFNL1 relative expression (log10) com-pared to controls (D0, all set at 1) from three independent experiments performed at least in duplicate (SeV) or four independentexperiments performed in duplicate (HBV). No robust IFNL1 expression was detected in HBV-infected samples (representative dotsare presented under the “detection limit” dotted line). (C,E) cGAS-related ISGs are not affected by HBV infection. HepG2-NTCPcells were infected with HBV or SeV. Alternatively, HepG2-NTCP cells were transfected with poly(I:C) (100 ng). Two days afterinfection or transfection, total RNA was extracted. Gene expression of IAR signature was then analyzed using multiplexed gene profil-ing. Results were analyzed by GSEA compared to nontransfected or noninfected controls (C) or by IFNB1 and IFI44 gene expression(log10) compared to nontransfected or noninfected controls (set at 1) (E). One experiment performed in triplicate is shown. (D,F)The cGAS expression level does not affect the cellular response to HBV infection. HepG2-NTCP-Cas9 (Cas9), HepG2-NTCP-KO_cGAS#2 (Ko_cGAS#2), HepG2-NTCP-Ctrl_ORF (Ctrl_ORF), and HepG2-NTCP-cGAS_OE (cGAS_OE) were infectedwith HBV. Two days after infection, total RNA was extracted. Gene expression of IAR signature gene set was then analyzed usingmultiplexed gene profiling. Results were analyzed by GSEA compared to nontransfected or noninfected controls (D) or by IFNB1and IFI44 gene expression (log10) compared to nontransfected or noninfected controls (set at 1) (F). One experiment performed intriplicate is shown.

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

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expression using digital multiplexed gene profiling(nCounter NanoString) and GSEA-based analysis.Whereas poly(I:C) transfection and SeV infectioninduced a marked modulation of cGAS effector/IARgene expression (FDR, 0.004 and <0.001, respec-tively), no significant modulation of IAR gene expres-sion was observed in HBV-infected cells (Fig. 2C), asfurther illustrated by the expression of IFNB1 andIFI44 (Fig. 2E). To measure the impact of cGASexpression on the cellular response to HBV infection,we then infected cGAS-depleted (KO_cGAS#2) andcGAS-overexpressing (cGAS_OE) HepG2-NTCPcells with HBV and analyzed the expression of thecGAS-related genes after infection. No significantmodulation of the IAR signature was observed inHBV-infected samples (Fig. 2D), as further illustratedby absent modulation of IFNB1 and IFI44 expression(Fig. 2F).To exclude the possibility that low HBV infection

could be the reason for the absence of IFN induction,we performed additional experiments using increasingMOIs. No induction of IFNB1 (Fig. 3A) was observedeven at an MOI of 10,000, despite very high infectionefficiency as shown by quantitation of pgRNA andimmunofluorescence of HBsAg (Fig. 3B,C). To inves-tigate whether IFN induction occurs potentially at a

very early step of viral infection and was missed in theexperimental design shown above, we performed atime course study of the IFN response to HBV withinthe first 24 hours postinfection. HBV infection did notinduce a measurable IFN response during early stepsof HBV infection (Fig. 3D). In contrast, SeV, anestablished inducer of IFN, showed robust inductionof IFN responses in HepG2-NTCP cells (Fig. 3D).Taken together, these data suggest an absence of sens-ing of HBV infection by the cGAS–STING pathwayin HepG2-NTCP cells.Because the HBV genome is packaged into the

nucleocapsid,(37) we investigated whether packagingshields virion DNA from cGAS recognition. We puri-fied HBV genomic rcDNA from HBV infectious par-ticles (Supporting Fig. S3) and transfected the nakedviral genome into HepG2-NTCP cells (1 lg, corre-sponding to approximately 106-107 HBV DNA cop-ies/lL). A significant (FDR, 0.02) induction of theIAR signature (illustrated by IFNB1 and IFI44 expres-sion, Fig. 4B) was observed after both rcDNA anddsDNA transfection, suggesting sensing of the nakedHBV genome (Fig. 4A). Interestingly, the number ofcellular HBV DNA copies was higher in HBV-infected cells compared to rcDNA-transfected cells(Fig. 4C), confirming that the levels of HBV DNA in

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 3. Impaired sensing of HBV infection at high MOIs or early time points of infection. (A-C) HepG2-NTCP cells were infectedwith HBV at increasing MOIs (0, 50, 500, and 10,000 GEq/cell) or transfected with poly(I:C) (100 ng). Two days after infection ortransfection, cells were lysed, total RNA was extracted, and IFNB1 expression (A) as well as HBV pgRNA levels (B) were quantifiedby quantitative RT-PCR. (A) Results are expressed as means 6 SD relative to IFNB1 expression (log10) compared to mock infectedcells (MOI 0, set at 1) from three independent experiments performed in triplicate. (B) Results are expressed means 6 SD relative toHBV pgRNA levels compared to mock infected cells (MOI 0, set at 100%) from three independent experiments performed in tripli-cate. Alternatively, HBV infection was assessed at 10 days postinfection by immunofluorescence of HBsAg (C). One representativeexperiment is shown. (D) HBV infection does not induce IFNB1 expression at early time points. HepG2-NTCP cells were eitherinfected by HBV or SeV or transfected with poly(I:C). Total RNA was extracted at 2, 6, 18, and 24 hours postinfection/posttransfec-tion, and IFNB1 expression was assessed by quantitative PCR. Results are expressed as means 6 SD relative to IFNB1 expression(log10) compared to naive cells (0, set at 1) from three independent experiments performed in triplicate.

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

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HBV-infected cells are sufficient to trigger IFN signal-ing and that the absence of HBV sensing in infectedcells was not due to low MOIs. Moreover, inductionof IAR gene expression was absent in HepG2-NTCP-KO_cGAS#2 cells, suggesting a cGAS-specific activa-tion of innate immunity by both dsDNA and rcDNAtransfection in our model.To validate these observations in a more physiological

model, we infected PHHs with HBV and controlledcGAS gene expression after 2 days of infection. Inter-estingly, while SeV strongly induced IAR gene expres-sion (Fig. 5B), a highly efficient HBV infection (Fig.5A) did not induce the expression of IAR genes (Fig.5B). In contrast, the transfection of rcDNA anddsRNA into PHHs from 4 different donors robustlytriggered the expression of IFNB1 and IFNL1 (Fig.5C), suggesting a robust sensing of viral DNA inhuman hepatocytes. Collectively, these data suggest thatnonencapsidated HBV DNA is sensed by cGAS butthat this sensing is impaired during HBV infection.

THE cGAS–STING PATHWAYEXHIBITS ROBUST ANTIVIRALACTIVITY AGAINST HBVINFECTION WITH REDUCTIONOF cccDNA LEVELS

Because cGAS exhibits antiviral activity against abroad range of DNA and RNA viruses (even in theabsence of direct viral sensing),(20) we then investigatedthe antiviral effect of the cGAS–STING signalingpathway in HBV infection. We silenced the expressionMB21D1, TMEM173 (encoding the STING pro-tein), TBK1, and IFI16 (another cytoplasmic DNAsensor able to directly activate STING(17)) in HepG2-NTCP cells prior to infection with HBV. Silencing ofMB21D1, TMEM173, and TBK1 expression induceda marked increase in HBV infection (Fig. 6A,B). Incontrast, the silencing of IFI16 had no effect on HBVinfection. CRISPR/Cas9-mediated KO or overexpres-sion of cGAS protein resulted in a marked increase ordecrease in HBV infection and HBV cccDNA lev-els—the key viral nucleic acid responsible for viral per-sistence (Fig. 6C-E). Notably, overexpression ofcGAS did not affect NTCP expression at the cell sur-face, suggesting that the susceptibilities of the differentcell lines to HBV infection are equivalent (SupportingFig. S4). Taken together, our results suggest thatcGAS is functional and exerts antiviral activity inHBV permissive cells.

HBV INFECTION INDUCESREPRESSION OF cGAS AND ITSEFFECTOR GENE EXPRESSION INCELL CULTURE AND IN LIVERCHIMERIC MICE

Because several reports have suggested that HBVproteins can inhibit IFN-signaling pathways,(16) wenext investigated whether HBV infection interferes withthe expression of cGAS-related genes by quantifyingMB21D1/cGAS mRNA and protein expression (Fig.7A,B). Interestingly, cGAS protein expression (Fig.7B) as well as expression of MB21D1, TMEM173, andTBK1 mRNA (Fig. 7C) were significantly inhibited inHBV-infected cells. To confirm this observation invivo, we then investigated the expression of humanMB21D1 expression in HBV-infected human liver chi-meric mice. MB21D1 was expressed at low but detect-able levels (Fig. 7D). MB21D1 expression wassignificantly (P 5 0.013) down-regulated in HBV-infected mice compared to noninfected control mice,confirming our results in the cell culture model (Fig.7E). Importantly, MB21D1 expression levels did notcorrelate with HBV genotype (Table 1). An absent cor-relation of human serum albumin with either MB21D1expression (Table 1 and Fig. 7E) or status of HBVinfection (Table 1; t test HBV versus control, P5 0.26)largely excludes the possibility that the observed differ-ences in cGAS expression are due to different humanhepatocyte repopulation levels or to a decrease of humanhepatocyte cell viability in individual animals. To inves-tigate whether HBV modulates cGAS effector function,we analyzed virus-induced changes on cGAS effectorgene expression using gene expression profiling in threecontrol mice and the three HBV-infected mice exhibit-ing the lowest levels of MB21D1 expression (Table 1).HBV infection resulted in a significant (FDR, 0.047)down-regulation of the expression of cGAS effectorgenes in human hepatocytes in chimeric mice (Fig. 7F).The data showed that HBV represses expression ofcGAS and its effector genes in vivo.

DiscussionThe interaction between HBV and the innate

immune system is a complex process that remains elu-sive and controversial.(15) Collectively, our data dem-onstrate that in human hepatocytes (1) naked HBVgenomic rcDNA is sensed in a cGAS-dependent man-ner, whereas the packaged HBV genome appears not

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to be recognized during viral infection; (2) the cGAS–STING pathway exhibits antiviral activity againstHBV infection including reduction of viral cccDNAlevels; (3) HBV infection suppresses both cGAS

expression and function in cell culture and humanizedliver chimeric mice.The detection of HBV DNA by the cellular sensors

within infected cells is still poorly understood and

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 5. Sensing of naked HBV rcDNA but not infectious HBV virions in PHHs. (A,B) HBV infection does not induce ISGexpression in PHHs. PHHs were treated with a preS1 peptide or a scrambled peptide (control) for 1 hour before infection withHBV. As positive controls, PHHs were transfected with poly(I:C) (100 ng) or infected with SeV (MOI �10). HBV infection ofPHHs was assessed 10 days postinfection by quantitative RT-PCR (A, left panel) or immunofluorescence (A, right panel). Quantita-tive RT-PCR results are expressed as means 6 SD ratio HBV pgRNA RNA/GAPDH mRNA from one experiment correspondingto the gene profiling experiment and performed in duplicate. Two days after infection, total RNA was extracted, and gene expressionof IAR was then analyzed using multiplexed gene profiling. Results were analyzed by GSEA compared to nontransfected control (B).One experiment in triplicate is shown. (C) Induction of IFBN1 and IFNL1 expression in PHHs. PHHs were transfected withdsDNA (4 lg) or HBV rcDNA (4 lg). IFNB1 and IFNL1 expression was assessed 24 hours after transfection by quantitative RT-PCR. Results are expressed as means 6 SD log10 IFNB1 or IFNL1 expression compared to nontransfected control cells (set at 1)from five independent experiments performed at least in duplicate. Abbreviation: DAPI, 4’,6-diamidino-2-phenylindole.

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 4. Sensing of HBV rcDNA in HepG2-NTCP cells. (A,B) Transfection of purified HBV rcDNA genome induces a cGAS-mediated innate immune response. HBV rcDNA was extracted from recombinant HBV virions as described in Patients and Methodsand quantified by quantitative PCR (Supporting Fig. S3). HBV rcDNA (1 lg) and positive control dsDNA (1 lg) were transfectedinto HepG2-NTCP-Cas9 and HepG2-NTCP-KO_cGAS#2 cells. Three days after transfection, total RNA was extracted. Geneexpression of IAR set was then analyzed using multiplexed gene profiling. The transcripts were analyzed by GSEA compared to non-transfected control (A) or by IFNB1 and IFI44 gene expression (log10) compared to nontransfected control (set at 1) (B). One experi-ment in triplicate is shown. (C) HBV DNA in HepG2-NTCP cells after rcDNA transfection and HBV infection are similar.HepG2-NTCP cells were infected with HBV or transfected with HBV rcDNA (1 lg). At day 2 after transfection/infection, DNAwas extracted and total HBV DNA was quantified by quantitative PCR. Results are expressed as means 6 SD total DNA copies permicrogram of total DNA (log10) from three independent experiments performed in triplicate (HBV infection) and two independentexperiments performed in triplicate (HBV rcDNA transfection).

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

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remains controversial. In vitro and in vivo datastrongly suggest that HBV behaves like a stealth virus,unable to trigger any innate immune response.(8,9,11)

Other studies have suggested that HBV-deriveddsDNA fragments(25) and viral nucleocapsid

destabilization and disassembly(38,39) could induceinnate immune responses. Our results demonstratethat in human hepatocytes—the natural target cell ofHBV infection—exposure of the naked HBV genomeleads to the activation of innate antiviral immune

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 6. Antiviral activity of cGAS results in reduction of HBV cccDNA. (A,B) Silencing of cGAS-related gene expression increasesHBV infection. siRNA targeting MB21D1 (sicGAS), TMEM173 (siSTING), TBK1 (siTBK1), or IFI16 (siIFI16) or a nontargetingsiRNA (siCtrl) were reverse-transfected into HepG2-NTCP cells 2 days prior to HBV infection. Silencing efficacy was assessed byquantitative RT-PCR 2 days after transfection (A). Results are expressed as means 6 SD percentage gene expression relative to siCtrl(set at 100%) from four independent experiments performed in technical duplicate. HBV infection was assessed by quantification ofHBV pgRNA by quantitative RT-PCR 10 days after infection (B). Results are expressed as means 6 SD percentage HBV pgRNAexpression relative to siCtrl (set at 100%) from four independent experiments performed in technical duplicate. (C) KO of MB21D1gene increases HBV infection. cGAS_KO#1, cGAS_KO#2, and control Cas9 cells were then infected with HBV; and viral infectionwas assessed 10 days after infection as described above. Results are expressed as means 6 SD percentage HBV pgRNA expression rel-ative to control cell line (Cas9, set at 100%) from three independent experiments performed in triplicate. (D) cGAS overexpressionreduces HBV infection. HepG2-NTCP cells were transduced with lentivirus encoding either a control plasmid (Ctrl_ORF) or a plas-mid encoding the full-length MB21D1 ORF (cGAS_OE). MB21D1 expression was assessed by quantitative RT-PCR (left panel).Results are expressed as means 6 SD percentage relative MB21D1 expression (log10) relative to control cell line (Ctrl_ORF, set at 1)from three independent experiments performed in duplicate. HepG2-NTCP, Ctrl_ORF, and cGAS_OE cells were then infectedwith HBV for 10 days, and HBV infection was assessed as described above. Results are expressed as means 6 SD percentage HBVpgRNA expression relative to control cell line (Ctrl_ORF, set at 100%) from three independent experiments performed in triplicate.(E) Detection of HBV cccDNA by Southern blot. HepG2-NTCP-derived cGAS_KO or cGAS_overexpressing cell lines wereinfected for 10 days with HBV. Total DNA from indicated HBV-infected cells was extracted, and HBV DNA was detected bySouthern blot. Two different DNA ladders (L1, L2) were used. XhoI digestion of DNA extracted from HBV-infected HepG2-NTCP-Cas9 cells was used as a control and resulted in a single 3.2-kb band (dsl HBV DNA). Mitochondrial DNA was detected asa loading control. One experiment is shown. Abbreviations: NS, nonsignificant; OE, overexpressing.

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

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responses. In contrast, sensing is largely absent duringHBV infection, most likely due to packaging into theviral capsid. These results extend a previous observa-tion in hepatoma cell lines transfected with replication-competent HBV DNA that the HBV genome itselfcan be recognized by the classical sensors.(25)

Interestingly, the capsid of HIV-1 also prevents thesensing of HIV cDNA by cGAS following reverse-

transcription up to integration, whereas HIV-2 capsidmay unmask the cDNA, leading to a stronger sensingby cGAS and a lower pathogenicity of the strain.(40)

Another explanation of this absence of sensingwould be the lack a functional STING protein in hep-atocytes, as has been recently reported.(41) In our study,rcDNA and dsDNA were sensed in a cGAS-dependent manner and able to activate the cGAS-

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

FIG. 7. HBV infection suppresses expression of the cGAS-related gene cell culture and humanized liver chimeric mice in vivo. (A-C) HepG2-NTCP cells were infected with HBV for 10 days. HBV infection was assessed by quantification of HBV pgRNA byquantitative RT-PCR. Results are expressed as means 6 SD from three experiments performed in triplicate. cGAS protein expressionwas assessed 10 days after infection (B, one experiment is shown). Gene expression relative to noninfected control cells of MB21D1,TMEM173, and TBK1 was assessed by quantitative RT-PCR at day 10 after infection (C). Results are expressed as means 6 SEMfrom three independent experiments performed in triplicate. (D,E) MB21D1 and IAR gene set expression is impaired in HBV-infected mice. uPA-SCID mice were infected with HBV for 16 weeks. Mice were then sacrificed, and HBV infection was assessed byHBV RNA–specific in situ hybridization (D) and quantification of HBV viral load in the serum (Table 1). Human MB21D1 expres-sion was detected in human hepatocytes by FISH from one HBV-infected mouse (D) and by quantitative RT-PCR from sevenHBV-infected mice and four control mice (E, left panel). Results are expressed as the ratio MB21D1 mRNA/GAPDH mRNA. Allindividual mice are presented as well as means 6 SD for each group (mock and HBV-infected mice). The level of MB21D1 expres-sion was independent of the viability of engrafted human hepatocytes as indicated by an absent correlation between MB21D1 expres-sion and human serum albumin expression in humanized mice (R2

5 0.231; E, right panel). (F) The IAR gene set was analyzedusing the nCounter NanoString in mice 6472, 6251, and 6254 (mock infected mice, Table 1) and 4766, 4771, and 4847 (HBV-infected mice, Table 1). A significant down-regulation (FDR, 0.047) of the gene set was observed in HBV-infected mice compared tocontrol mice. Individual Z scores for the genes significantly modulated between the two groups according to GSEA are presented.Negative Z score (blue) and positive Z score (red) correspond to repression and induction of the indicated genes, respectively. Abbre-viation: Dpi, days postinfection.

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �

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VERRIER, YIM, ET AL. HEPATOLOGY, November 2018

mediated antiviral response in HepG2-NTCP cells(Fig. 4). Moreover, we detected STING at the proteinlevel, in accordance with a recent study(42); and specificsilencing of TMEM173 (STING) expression wasassociated with a significant increase in HBV infection(Fig. 6). Consequently, it is likely that STING is func-tionally active in HepG2 cells. The observed HBVDNA sensing in PHHs (Fig. 5) suggests that the for-eign DNA detection pathways are active in PHHs aswell. This observed innate immune response despiteweak STING expression may suggest a STING-independent activity of cGAS, as has been recentlyreported,(43) including in hepatocytes.(44) To under-stand the impact of cGAS and STING expression onthe innate immune response to HBV infection, itwould be of further interest to analyze the HBV-induced modulation of gene expression in Kupffer cellsfollowing phagocytosis as they exhibit higher STINGand cGAS levels compared to hepatocytes(41,45) andrespond to HBV infection.(11) In the same vein,cGAMP has been shown to be packaged in viral par-ticles.(46) It would be of interest to determine whetherHBV particles can incorporate cGAMP during viralassembly and to test their ability to stimulate other celltypes through this indirect pathway.Moreover, our results show conclusively that cGAS

basal expression has antiviral activity against HBVinfection including reduction of viral cccDNA. Thisfinding extends previous studies showing that cGAS

exhibited antiviral activity against a broad range ofRNA and DNA viruses(20) and that the cGAS–STING pathway can impair HBV replication andassembly in transfection studies.(24,25) Schoggins andcolleagues proposed that expression of cGAS may beresponsible for the establishment of a basal antivirallevel in cells through its activation by an unknownligand. cGAS-depleted cells may then be more suscep-tible to viral infections through the down-regulation ofthe basal level of innate antiviral genes.(20)

Given its antiviral function, cGAS is a target ofchoice for viruses in order to evade immune responses.It has been reported that the Kaposi’s sarcoma–associ-ated herpesvirus negatively regulated the cGAS-dependent signaling pathway.(47,48) In the same vein,HBV viral proteins have been shown to interfere withthe Janus kinase–signal transducer and activator of tran-scription signaling pathway.(16) Our data suggest thatHBV can repress expression of the cGAS and its relatedgenes, such asMB21D1, TMEM173, and TBK1. Moreinterestingly, MB21D1 expression was down-regulatedin the liver of HBV-infected mice, validating the rele-vance of these findings in vivo. It still needs to be deter-mined whether HBV can directly target cGAS andcGAS-related factors for an active inhibition of this sig-naling pathway. A recent study elegantly demonstratedan active inhibition of the cGAS pathway by denguevirus through nonstructural protein 2B.(49) On the otherhand, MB21D1 (as a classical member of theISGs(20,36)) down-regulation may be the consequence ofglobal inhibition of the canonical IFN pathways byHBV, as suggested by some investigators(16,50) but notby others.(11,13,14) Given the antiviral activity of thecGAS-signaling pathway against HBV including reduc-tion of HBV cccDNA (Fig. 6),(24,25) the virus-mediatedrestriction of MB21D1 expression may play an addi-tional role in HBV immune evasion.

Acknowledgment: We thank D. Garcin (University ofGeneva, Geneva, Switzerland) for providing the SeVinoculum; D. Calabrese, S. Wieland, and M. Heim(University of Basel, Basel, Switzerland) for theFISH analyses and helpful discussions; F. Zhang(Broad Institute of MIT and Harvard, Cambridge,MA) for lentiCas9-Blast and lentiGuide-Puro plas-mids; C. Thumann, N. Brignon, and M. Oudot(Inserm UMRS_1110) for excellent technical sup-port; and J.M. Rous�ee (Laboratoire Schuh-groupement Bio 67, Strasbourg, France) for thequantification of HBV loads in sera of humanizedmice.

TABLE 1. cGAS Expression in HBV-Infected Human LiverChimeric Mice

MouseAlbumin(lg/mL)

HBV(IU/mL)

MB21D1mRNA

Control 6410 1,280 — 1.40E-03

6472 2,720 — 1.40E-03

6251 3,240 — 2.30E-03

6254 7,870 — 1.90E-03

HBV

Gt E 4770 4,200 2.9E107 1.30E-03

4773 4,800 1.5E108 1.70E-03

4766 12,760 3.6E106 3.20E-04

4771 13,120 6.2E105 3.70E-04

Gt D 4846 2,127 5.5E105 3.80E-04

4847 10,045 1.6E108 1.70E-04

4848 1,992 6.7E106 7.50E-04

Levels of human albumin, HBV viral load, and MB21D1 in livertissue from HBV-infected and control mice are shown. MB21D1expression is normalized to GAPDH expression. The HBV geno-type is indicated. Bold indicates mice used for multiplexed geneprofiling.Abbreviation: Gt, genotype.

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Author names in bold designate shared co-first authorship.

Supporting InformationAdditional Supporting Information may be found at

onlinelibrary.wiley.com/doi/10.1002/hep.30054/suppinfo.

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158 Verrier ER, et al. Gut 2020;69:158–167. doi:10.1136/gutjnl-2018-317065

Hepatology

ORIGINAL ARTICLE

Combined small molecule and loss- of- function screen uncovers estrogen receptor alpha and CAD as host factors for HDV infection and antiviral targets

Eloi R Verrier,1 Amélie Weiss,2 Charlotte Bach,1 Laura Heydmann,1 Vincent Turon- Lagot,1 Arnaud Kopp,2 Houssein El Saghire,1 Emilie Crouchet,1 Patrick Pessaux ,1,3 Thomas Garcia,4 Patrick Pale,4 Mirjam B Zeisel,1 Camille Sureau,5 Catherine Schuster,1 Laurent Brino,2 Thomas F Baumert 1,3,6

To cite: Verrier ER, Weiss A, Bach C, et al. Gut 2020;69:158–167.

1Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000 Strasbourg, France2IGBMC, Plateforme de Criblage Haut- débit, UMR7104 CNRS U1258 Inserm, Illkirch, France3Institut Hospitalo- universitaire, Pôle Hépato- digestif, Nouvel Hôpital Civil, Strasbourg, France4Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, UMR 7177 CNRS, Université de Strasbourg, Strasbourg, France5INTS, Laboratoire de Virologie Moléculaire, Paris, France6Institut Universitaire de France, Paris, France

Correspondence toDr Eloi R Verrier and Pr Thomas F Baumert, Inserm UMR_S1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 3 rue Koeberlé, 67000 Strasbourg, France; e. verrier@ unistra. fr, thomas. baumert@ unistra. fr

Received 26 June 2018Revised 24 January 2019Accepted 10 February 2019Published Online First 4 March 2019

© Author(s) (or their employer(s)) 2020. Re- use permitted under CC BY- NC. No commercial re- use. See rights and permissions. Published by BMJ.

Significance of this study

What is already known on this subject? Chronic hepatitis D is the most severe form of viral hepatitis. Efficient therapeutic strategies are absent. Hepatitis D virus is a small hepatitis B virus satellite virus. Knowledge about HDV–hepatocyte interactions is limited. HDV host- dependency factors are largely unknown.

What are the new findings? A RNAi screen identified oestrogen receptor 1 (ESR1) and CAD as novel host factors for HDV infection. The inhibition of CAD restricts HDV infection through uridine depletion. ESR1 and CAD are functionally linked by transcriptional activation of gene expression. ESR1 and CAD inhibitors fulvestrant and PALA, respectively, specifically inhibit HDV replication in a dose- dependent manner in human hepatocytes. CAD and ESR1 are previously undiscovered targets for antiviral therapies.

How might it impact on clinical practice in the foreseeable future? The discovery of HDV host- dependency factors opens the door for novel therapeutic strategies against chronic hepatitis D - a major unmet medical need. Fulvestrant and PALA- like molecules are candidate compounds for HDV antivirals to enter preclinical development.

ABSTRACTObjective Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent.Design Here, we combined an RNAi loss- of- function and small molecule screen to uncover host- dependency factors for HDV infection.Results Functional screening unravelled the hypoxia- inducible factor (HIF)- signalling and insulin- resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus- hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl- phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by ESR1) as key host factors for HDV life cycle. Mechanistic studies revealed that the two host factors are required for viral replication. Inhibition studies using N- (phosphonoacetyl)- L- aspartic acid and fulvestrant, specific CAD and ESR1 inhibitors, respectively, uncovered their impact as antiviral targets.Conclusion The discovery of HDV host- dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.

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159Verrier ER, et al. Gut 2020;69:158–167. doi:10.1136/gutjnl-2018-317065

Hepatology

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160 Verrier ER, et al. Gut 2020;69:158–167. doi:10.1136/gutjnl-2018-317065

Hepatology

Figure 1 Identification of host- dependency factors for HDV infection using a high- throughput RNAi screen. (A). Approach with flow chart of the screen. NTCP- overexpressing Huh7 cells (termed Huh-106) were transfected with pools of four siRNAs per target of the Dharmacon ‘Druggable genome’ library 48 hours before HDV infection. Infection was assessed after 7 days by immunofluorescence. Each siRNA pool was tested in triplicate. As controls, Huh-106 cells were transfected with a non- targeting siRNA control (siCtrl), siRNA targeting SLC10A1 (siNTCP) and PLK1 (siPLK1, lethal for the cells) expression. Representative images of HDV infection in Huh-106 cells from the primary screen are shown in B. As readout for infection, cells were stained with an anti- HDAg antibody and cell nuclei were stained with 4′,6- diamidino-2- phenylindole (DAPI). (C) General effect of the siNTCP on HDV infection at the screen level. Results are expressed as means ± SD % HDV- positive cells from siCtrl- treated cells (n=318) and siNTCP- treated cells (n=265). ***p value <0.001 (unpaired Student’s t- test). (D). Distribution of host- factor candidates according to their inhibitory effect on HDV infection. The top 5% (% HDV positive cells <8.3) were selected as candidates for further work- up. (E). Selection of candidate genes from the primary screen. From the 311 genes inducing a >45% decrease in HDV infection after silencing, candidate genes were selected depending on their robustness (p value and false discoery rate (FDR) <0.05), their expression in the liver (Illumina Body Map tool) and their toxicity. Toxicity was evaluated as the percentage of viability compared with the siCtrl, quantified by counting the DAPI- positive nuclei in the wells at the end of infection. From the 194 selected candidates, RNF130 was present twice (subset 8 and subset 10), and two pseudogenes (tAKR/AKR1C6P and LOC402164) were removed. One hundred and ninety- one candidates (top 2.5%) were further worked up. HDV, hepatitis D virus; NTCP, sodium taurocholate cotransporting polypeptide.

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Hepatology

Figure 2 Pathway analysis of HDV host factors identified within the RNAi screen. The identified host genes were subjected to functional enrichment pathway analysis through ToppGene Suite (https://toppgene.cchmc.org) using Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Pathways scoring at a FDR value of < 0.05 were considered significant. (A) Representation of the number of genes and FDR values of different KEGG pathways significantly enriched within the primary siRNA screen candidates. (B) Individual genes contributing to the enrichment of the significant KEGG pathways were further analyzed for protein- protein interactions using STRING database. Interaction networks were represented using Cytoscape 3.6.0.

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Hepatology

Figure 3 CAD is a key host factor required for HDV infection. (A) Functional validation of host factors belonging to the pyrimidine biosynthesis using perturbation studies. Results are presented as means ± SD % HDV infection compared with control siRNA (siCtrl, set at 100%) from three independent screens (n=9, primary screen and two validation screens performed in triplicate). ***p value <0.001 (unpaired Student’s t- test compared with siCtrl samples). (B–D) CAD is required for HDV infection. Huh-106 cells were reverse- transfected with four individual siRNAs targeting CAD mRNA or with the pool of four siRNAs. Silencing efficacy was assessed by western blot after 2 days. (B) One representative experiment is shown. Cells were then infected with HDV, and virus infection was assessed after 7 days by quantitative reverse transcription (qRT)- PCR. Results are expressed as means ± SEM % HDV infection compared with siCtrl (set at 100%) from three independent experiments (n=8). (C) Alternatively, HDV infection was assessed by immunofluorescence (IF) using a patient- derived anti- HDAg antibody. (D) One representative experiment using the pool of siCAD is shown. (E) HDV infection has no effect on CAD expression in PHH. PHH were treated with preS1 peptide (preS1) or a peptide control (Ctrl) for 1 hour prior to infection with HDV for 7 days. Results are expressed as means ± SD % HDV infection (assessed by HDV RNA levels) or CAD expression compared with control peptide- treated cells (Ctrl, set at 100%) from four independent experiments (n=8). (F–G) The CAD inhibitor PALA dose- dependently inhibits HDV infection in Huh-106 cells (F) and PHH (G). Cells were treated with PALA at the indicated concentrations 24 hours before infection with HDV. Cells were then cultured for 7 days in presence of PALA. HDV infection was assessed by qRT- PCR. Cell viability was assessed by Presto Blue. Results are expressed as means ± SD % HDV infection or cell viability compared with untreated cells (0, set at 100%) from three independent experiments (Huh-106 [F], n=9) or as means ± SEM % HDV infection or cell viability from three independent experiments (PHH [G], n=8). CAD, carbamoyl- phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase; HDV, hepatitis D virus; PALA, N- (phosphonoa cetyl)- L- aspartic acid; PHH, primary human hepatocyte.

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Hepatology

Figure 4 Characterisation of CAD–HDV functional interaction. (A–C) Uridine complementation restores HDV infection in PALA- treated cells. Huh-106 cells were treated with PALA (1 µM or 10 µM) in presence or absence of 30 µM uridine 24 hours prior to infection with HDV, and compound treatment was maintained for 7 days. HDV infection was assessed by northern blot (A). HDV+ corresponds to approximately 5.107 HDV RNA genome equivalents extracted from HDV particles produced in Huh7 cells. rRNA corresponds to ribosomal RNA. One representative experiment is shown. Alternatively, Huh-106 cells were treated with PALA 2.5 µM in presence or absence of 30 µM uridine. HDV infection was assessed after 7 days by IF (B) or qRT- PCR (C). Results are expressed as means ± SEM % HDV infection compared with HDV- infected untreated cells (Ctrl, set at 100%) from three independent experiments (n=6). (D) Absent direct interaction between HDV antigens and CAD. Huh-106 were transfected with pSVL(D3) plasmid encoding the HDV genome. Three days after transfection, cells were lysed, and HDAg- specific co- immunoprecipitation (co- IP) was performed using an anti- HDAg antibody (Delta) or with a control antibody (Ctrl). HDV antigens and CAD expression in the original cell lysate (input), in Flow- through control samples (FT) and in IP eluates (IP) were assessed by western blot. One experiment is shown. (E) No IFN induction after inhibition of pyrimidine biosynthesis in Huh-106 cells. Huh-106 cells were treated with Brequinar or PALA at the indicated concentrations. Alternatively, Huh-106 cells were reverse- transfected with Poly(I:C) (100 ng). Cells were then lysed every day for 3 days, and IFNB1 expression was assessed by qRT- PCR. Results are expressed as means ± SD relative IFNB1 expression (log10) compared with untreated or non- transfected cells (0, all set at 1) from three independent experiments (n=6). CAD, carbamoyl- phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase; HDV, hepatitis D virus; PALA, N- (phosphonoacetyl)- L- aspartic acid.

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Figure 5 PALA specifically inhibits HDV replication by targeting CAD biological function. (A) Schematic representation of reactions catalysed by CAD enzyme. (B) DHO treatment restores HDV infection in PALA- treated cells. Huh-106 cells were treated with PALA 2.5 µM and infected with HDV in presence or absence of L- glutamine (Glu) or DHO at the indicated concentrations. Infection was assessed after 7 days by northern blot detection of HDV genomic RNA. rRNA corresponds to ribosomal RNA. One experiment is shown. (C) PALA inhibits both HDV genomic and antigenomic production. Huh-106 cells were treated with PALA 2.5 µM 24 hours prior to infection with HDV. HDV genomic and antigenomic RNAs were detected by northern blot using specific probes 7 days after infection. HDV+ corresponds to approximately 5.107 HDV RNA genome equivalents extracted from HDV particles produced in Huh7 cells. One experiment is shown. (D) Kinetics of HDV infection by PALA. Huh-106 cells were pretreated with PALA at 2.5 µM and infected with HDV (conditions P#1 and P#2). Cells were then cultured in presence of PALA for 48 hours (P#1) or for 7 days (P#2) in presence or absence of uridine (30 µM). Alternatively, Huh-106 cells were infected with HDV with no PALA pretreatment (P#3). Sixteen hours after viral inoculation, cells were cultured in presence of PALA 2.5 µM with or without uridine (30 µM). HDV infection was assessed after 7 days by qRT- PCR. Results are expressed as means ± SEM % HDV infection compared with HDV- infected untreated cells (Ctrl, set at 100%) from three independent experiments (n=6). (E) PALA does not affect HDV binding. Huh-106 cells were cultured for 24 hours at 16°C in presence of HDV particles, which were pretreated or not with heparin (30 µg/mL). HDV binding was measured by qRT- PCR quantification of total HDV RNA bound to cells after 24 hours. Results are expressed as means ± SD % HDV binding relative to control untreated cells (Ctrl, set at 100%) from three independent experiments (n=9). (F–H) CAD inhibition or silencing does not affect HBV infection and replication. (F) HBV- producing HepAD38 cells were treated with PALA (10 µM) for 3 days. HBeAg and HBsAg secretion in culture supernatant was then quantified by chemiluminescent immunoassay (CLIA). Cell viability was assessed by Presto Blue. Results are expressed as means ± SEM % HBeAg production, HBsAg production or cell viability compared with untreated cells (0 µM, all set at 100%) from three independent experiments (n=6). (G) HepAD38 cells were treated with either tenofovir (TFV) or PALA at the indicated concentrations for 3 days. HBV replication was assessed by quantification of HBV DNA copies in the supernatant of treated cells by qPCR. Results are expressed as means ± SD % HBV DNA in the supernatant or cell viability compared with untreated cells (Ctrl, all set at 100%) from three independent experiments (n=9). (H) HepG2- NTCP cells were reverse- transfected with siCAD or siCtrl for 2 days prior to infection with HBV. HBV infection was assessed after 10 days by quantification of HBeAg and HBsAg production using chemiluminescent immunoassay (CLIA). Results are expressed as means ± SD % CAD expression, HBeAg production or HBsAg production compared with siCtrl- transfected cells (siCtrl, all set at 100%) from three independent experiments (n=6). CA, Carbamoyl aspartic acid; CAD, carbamoyl- phosphate synthetase 2, aspartate transcarbamylase and dihydroorotase; DHO: dihydroorotate; Glu, glutamine; HBV, hepatitis B virus; HDV, hepatitis D virus; PALA, N- (phosphonoacetyl)- L- aspartic acid; Pi, inorganic phosphate; UMP, uridine monophosphate.

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Hepatology

Figure 6 ESR1 inhibitor fulvestrant inhibits HDV replication by suppression of CAD expression. (A) Small molecule screen flow chart. Huh-106 cells were treated with individual compounds belonging to the Prestwick chemical library (10 µM) 1 day prior to infection with HDV. Infection was assessed after 7 days by immunofluorescence. Every compound was tested in triplicate. (B). ESR1 modulators affect HDV infection. From the primary screen, fulvestrant (an ESR1 inhibitor) from the one hand, and tamoxifen and toremifen from the other hand (two agonists/modulators of ESR1) exhibited antiviral or proviral activity against HDV, respectively. Results are presented as means ± SD % HDV infected cells (n=3). (C). Fulvestrant dose- dependently inhibits HDV infection. Huh-106 cells were treated with fulvestrant at the indicated concentrations and then infected with HDV for 7 days. Results are expressed as means ± SD % HDV infected cells from three independent experiments (n=9). (D) Short fulvestrant treatment for 48 hours following virus inoculation inhibits HDV infection. Huh-106 cells were infected with HDV and then treated with fulvestrant (10 µM) or dimethyl sulfoxide (DMSO) for 48 hours. Cells were then cultured in absence of drug and infection was assessed after 7 days by IF. One representative experiment is shown. (E) Fulvestrant antiviral activity is associated with slight cytotoxicity. Cell viability was assessed after 48 hours and after 7 days by Presto blue. HDV infection was assessed after 7 days by qRT- PCR. Results are expressed as means ± SD % HDV infection (HDV RNA) or cell viability compared with untreated HDV- infected cells (Ctrl, set at 100%) from three independent experiments (n=9). (F) Fulvestrant antiviral activity in PHH. PHH were infected with HDV, and then treated with fulvestrant for 48 hours at the indicated concentrations. Results are expressed as means ± SD % HDV infection (HDV RNA) or cell viability compared with untreated HDV- infected PHH (Ctrl, set at 100%) from two independent experiments (n=6). (G) Fulvestrant inhibits CAD expression. Huh-106 cells and PHH were treated with fulvestrant (Fulv, 10 µM) or DMSO for 72 hours. CAD expression was assessed by western blot. CAD, carbamoyl- phosphate synthetase 2, aspartate transcarbamylase  and dihydroorotase; HDV, hepatitis D virus; ESR1, estrogen receptor 1; PHH, primary human hepatocyte.

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Hepatology

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Validation of CAD as a HDV host factor using individual siRNAs!-58>ER( 4"**'( ;","( ,"+",'"8(%,$2'3"4%")( ;&%5( %5"( 37-,( &2)&8+&)-$*('&TP?'(3,76(%5"('&K?/(#77*A($(#77*(73('&TP?(%$,@"%&2@(V]K>E?>( .'&PGKW1( 7,( $( 2728(%$,@"%&2@( '&TP?( 472%,7*( .'&K%,*1(-'&2@(*&#73"4%$6&2(TP?&(6$I($'()"'4,&:")=U(BE(X"2"("I#,"''&72(;$'($''"''")A(F()$9'($3%",(%,$2'3"4%&72A(:9(;"'%",2(:*7%()"%"4%&72(73(K?/(#,7%"&2(-'&2@($(,$::&%(67274*72$*($2%&8(K?/($2%&:7)9(.?:4$6($:QEYEE1($'(#,"+&7-'*9()"'4,&:")=U(BE(β8$4%&2("I#,"''&72(;$'($''"''")($'($(*7$)&2@(472%,7*(-'&2@($(67-'"(67274*72$*($2%&8β8$4%&2( $2%&:7)9( .V&@6$A(?BQQ>1=(G;7()$9'( $3%",( %,$2'3"4%&72A(4"**'(;","( &23"4%")(:9(!/0A($2)(&23"4%&72(;$'($''"''")($3%",(U()$9'($'()"'4,&:")(&2(72*&2"('-##*"6"2%$,9(6$%",&$*($2)(6"%57)'=

Statistical analysis?**( "I#",&6"2%'(;","(#",37,6")( $%( *"$'%( %;&4"( &2( $2( &2)"#"28)"2%(6$22",=(V%$%&'%&4$*( $2$*9'"'(;","(#",37,6")(-'&2@($( %;78(%$&*")(M$228( 5&%2"9(a(%"'%(-2*"''(7%5",;&'"('%$%")e(6kE=EB(.l1A(6kE=E>( .ll1( $2)( 6kE=EE>( .lll1( ;","( 472'&)",")( '%$%&'%&4$**9('&@2&3&4$2%=(V&@2&3&4$2%(#(+$*-"'($,"(&2)&4$%")(:9($'%",&'H'(&2(%5"(&2)&+&)-$*(3&@-,"'($2)(3&@-,"(*"@"2)'=(G5"(2-6:",(73(:&7*7@&4$*(,"#*&4$%"'(&'(&2)&4$%")(&2(%5"(3&@-,"(*"@"2)'(.21=?))&%&72$*(6"%57)7*7@&4$*(&237,6$%&72($,"($+$&*$:*"(&2(72*&2"(

'-##*"6"2%$,9(6$%",&$*=

Acknowledgements We would like to thank J Taylor (Fox Chase Cancer Center) for the gift of the HDV expression plasmid (pSVL(D3)) and our colleagues S Durand and M Renaud for excellent technical support. We thank the INGESTEM infrastructure for access to the IGBMC high- throughput high- content screening workstation.

Contributors TB initiated the study. TB and ERV designed and supervised research. ERV, AW, LB and TB set up, designed and performed the siRNA and small molecule screens. TG and PPa produced the sparfosic acid. ERV, CB, LH, VT- L and EC performed the validation experiments. CSu performed the HDV northern blots. PPe provided human hepatocytes. ERV, AW, CB, LH, EC, MBZ, CSu, CSc, LB and TB analysed the data. ERV, HES and AK performed the bioinformatical analyses of the screens. EV and TB wrote the manuscript. All the authors approved the study.

Funding This work was supported by Inserm, the University of Strasbourg, the European Union (Infect- ERA hepBccc, ERC-2014- AdG-671231- HEPCIR and Horizon 2020 research and innovation programme under grant agreement 667273 - HEPCAR), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS 15/1099) and the French Cancer Agency (ARC IHU201301187). This work has been published under the framework of the LabEx ANR-10- LAB-28 and benefits from a funding from the state managed by the French National Research Agency as part of the Investments for the Future (Investissements d’Avenir) programme. ERV is the recipient of an ANRS fellowship (ECTZ50121).

Competing interests None declared.

Ethics approval Protocols were approved by the local Ethics Committee of the Strasbourg University Hospitals (CPP) and the Ministry of Higher Education and Research of France (DC 2016 2616).

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement The datasets generated in this study, including the results from both RNAi and small molecule primary screens, are available within online supplementary material files. The rest of the data are available from the corresponding authors on reasonable request.

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non- commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non- commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.

ORCID iDsPatrick Pessaux http:// orcid. org/ 0000- 0001- 5635- 7437Thomas F Baumert http:// orcid. org/ 0000- 0002- 9022- 5611

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= VIR Article Identification = 0776 Date: June 11, 2019 Time: 5:39 pm

Revue

Virologie 2019, 23 (3) : 149­59

Virus de l’hépatite D : cycle viral et nouvellesstratégies thérapeutiques

Vincent Turon­LagotAntonio SavianoCatherine SchusterÉloi R. Verrier

Université de Strasbourg, Inserm,

Institut de recherche sur les maladies

virales et hépatiques UMR_S1110,

F­67000 Strasbourg, France

Résumé. De récentes estimations suggèrent qu’environ 70millions de personnessont infectées par le virus de l’hépatite D (ou delta, HDV). HDV est un petit virussatellite du virus de l’hépatite B (HBV) capable d’achever son cycle viral unique-ment en présence de ce dernier. L’hépatite D est la forme la plus sévère d’hépatitevirale chronique. Elle est responsable d’une aggravation et d’une accélération dela progression de lamaladie hépatique, en comparaison des patientsmonoinfectéspar le HBV. Les traitements actuels, basés sur l’interféron pégylé sont peu effi-caces et ne permettent que rarement l’élimination définitive du virus. L’absenced’un modèle d’étude simple a longtemps enfreint la compréhension des inter-actions HDV-hépatocytes, et notamment l’identification de facteurs hépatiquesimpliqués dans le cycle viral. Ces facteurs sont des cibles d’intérêt pour le déve-loppement de nouvelles stratégies thérapeutiques dont certaines sont en coursd’essai clinique. Cette revue résume les connaissances actuelles de la virologiemoléculaire du HDV et fait le point sur les nouvelles solutions thérapeutiques encours de développement.

Mots clés : HDV, virus hépatiques, stratégies antivirales

Abstract. An estimated 70 million people are chronically infected with hepati-tis D (delta) virus (HDV) worldwide. HDV is a small satellite virus of hepatitisB virus (HBV) requiring HBV for the completion of its cycle. Hepatitis D isthe most severe form of chronic viral hepatitis. It is responsible for an accelera-tion and an aggravation of chronic liver disease compared to HBV monoinfectedpatients. Current treatments based on pegylated interferon rarely allow viral clea-rance in chronically infected patients. For long time, the absence of easy-to-usemodels has limited the knowledge on virus-host interactions. Notably, hepato-cyte host factors involved in the viral life cycle remain largely unknown. Thesehost factors are potential therapeutic targets for novel treatment strategies, inclu-ding molecules currently evaluated in clinical trials. This review summarizesour knowledge on HDVmolecular virology and innovative therapeutic strategiestargeting hepatocyte host factors.

Key words: HDV, hepatotropic viruses, antiviral strategies

Introduction : épidémiologie

L’hépatite D ou delta est considérée comme la forme la plussévère d’hépatite virale chronique. Identifié initialementchez des patients atteints d’hépatite B chronique (HBC)comme un nouvel antigène du virus de l’hépatite B (HBVpour hepatitis B virus) [1], l’agent pathogène responsableest un petit virus à ARN infectant exclusivement les

Correspondance : E.R. Verrier<[email protected]>

hépatocytes et nécessitant la présence de HBV pourachever son cycle réplicatif [2, 3]. Identifié aujourd’huicomme le plus petit virus capable d’infecter les animaux,le virus de l’hépatite D (HDV pour hepatitis D virus) estresponsable d’une accélération et d’une aggravation dela progression de la maladie hépatique chez les patientssouffrant d’HBC [4], déjà première cause mondialede carcinome hépatocellulaire [5]. Initialement, il étaitestimé que l’hépatite D touchait environ 5 % des patientschroniquement infectés par le HBV, soit entre 15 et20 millions de patients dans le monde [4]. Une récented

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Virologie, Vol 23, n◦ 3, mai-juin 2019 149Pour citer cet article : Turon-LagotV, SavianoA, Schuster C,Verrier ÉR.Virus de l’hépatiteD : cycle viral et nouvelles stratégies thérapeutiques.Virologie 2019; 23(3) : 149-59 doi:10.1684/vir.2019.0776

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A B

S

L

M

ARN génomique

ADAR1AgHBs

ARN génomique

S-AgHD

L-AgHD

UAG

ARN antigénomique

ARNm AgHD

ribozyme

ribozyme

AAAAA3’5’

AgHD ORF

U|G

Figure 1. Structure du virus de l’hépatite D (HDV). (A) Représentation schématique de la particule virale du HDV. Le virion est composéd’une enveloppe lipidique dans laquelle sont enchâssées les trois formes des protéines d’enveloppe du virus de l’hépatite B (HBV) quiforment l’AgHBs (S, M et L). Le génome du HDV est composé d’un ARN simple brin circulaire à polarité négative entouré par les deux formesde l’antigène delta (L­AgHD et S­AgHD) formant le complexe ribonucléoprotéique. (B) Le génome du HDV est fortement apparié (> 70 %d’appariement) induisant une structure en bâtonnet. Il contient une séquence ribozyme qui catalyse la fragmentation des différentes unitésde génome produites au cours de la réplication en cercles roulants. La transcription de l’ARN génomique permet la synthèse de deuxARNs différents : l’ARN antigénomique et l’ARNm AgHD. L’ARN antigénomique contient également une séquence ribozyme et permet lanéosynthèse d’ARN génomique. Il contient également un site d’édition. L’enzyme ADAR1 catalyse la modification d’une adénosine (A) ducodon stop de l’ORF S­AgHD en inosine (I). Cette édition de l’ARN induit la production de la seconde forme de AgHD, plus longue de19 acides aminés.

méta-analyse présente une prévalence mondiale de 0,98 %inégalement répartie à travers le globe, correspondant àune prévalence de 10,58 % chez les patients HBV [6].Même si les deux chiffres sont difficilement conciliables(de 62 millions à 27 millions de patients en fonction del’approche), cette étude suggère un nombre de patientsinfectés par le HDV dans le monde bien plus important queles études précédentes. Certaines régions telles le bassinméditerranéen (27,8 % des patients atteints d’hépatite) [7],l’Afrique du Nord (20,7 % des patients atteints d’hépatite)[8] et l’Afrique centrale (38 % des patients atteintsd’hépatite) [9] sont particulièrement touchées. En Europeet aux États-Unis, une majorité de patients infectés par leHDV sont des usagers de drogue injectable [6]. En dépit dela généralisation de la vaccination anti-HBV, la prévalencedu HDV augmente dans les pays développés, ce rebondétant notamment dû à l’immigration depuis les régionsendémiques mais également au manque de vigilance despopulations à risque à l’égard des virus hépatiques [10].À l’heure actuelle, aucun traitement ne permet efficacementd’éliminer le virus [4]. La recherche de nouvelles solu-tions thérapeutiques a longtemps été freinée par le manquede connaissances des interactions HDV-hépatocytes, engrande partie dû à l’absence de modèle d’étude simple. Desdécouvertes récentes sont à l’origine d’avancées significa-tives dans la compréhension du cycle viral, notamment dans

l’identification de nouveaux facteurs hépatiques impliquésdans le cycle viral, donnant lieu à l’émergence de nouvellesstratégies de traitement, dont certaines sont actuellementtestées en essai clinique.

Virologie moléculaire du HDV

Structure des virions

Le HDV est un petit virus enveloppé satellite du HBVd’environ 35 nm de diamètre (figure 1) [2]. Il est caractérisépar la présence d’une enveloppe comportant les antigènesde surface du HBV (AgHBs), indispensables à la forma-tion des particules virales, qui contient le génome viralcirculaire associé aux deux formes de l’antigène delta(AgHD) formant un complexe ribonucléoprotéique (RNP)[2, 11]. Cet ARN circulaire de polarité négative permetl’expression d’ARNm codant pour les formes, courte (S-AgHD) et longue (L-AgHD) de l’antigène delta, toutesdeux impliquées dans le cycle réplicatif et la formationde la RNP virale [4]. Cette structure très particulière luiconfère une place à part dans la classification des virus,seul représentant du genre non classé des Deltavirus. LeHDV est décliné en 8 génotypes hétérogènes inégalementrépartis sur l’ensemble du globe [12]. Si le génotype 1 estretrouvé dans le monde entier, les génotypes 5 et 8 prédo-

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minent en Afrique. Les génotypes 2 et 4, associés à unemaladie hépatique moins agressive [13] sont retrouvés enExtrême-Orient. Enfin, le génotype 3, associé à un risqueaccru d’insuffisance hépatique est principalement présenten Amérique du Sud [12, 13].

Origine du HDV : évolution depuis un viroïde

de plante ou d’un ARN cellulaire ?

L’origine du HDV n’est à ce jour pas connue maisdeux hypothèses majeures coexistent depuis une vingtained’années et proposent que HDV dérive soit de viroïdes deplantes soit d’un ARNm cellulaire.Parmi les caractéristiques du génome du HDV, sa struc-ture circulaire et son fort taux d’appariement (figure 1B)le rapprochent fortement des génomes de viroïdes deplante, petits ARN circulaires simple brin à haut potentielréplicatif, de taille cependant bien inférieure au génomedu HDV, comprise entre 250 et 400 nucléotides [14-16]. Une autre différence notable est la présence surl’antigénome du HDV d’un cadre ouvert de lecture codantpour l’antigène delta, alors que les génomes de viroïdes (àl’exception du scRYMV [17]) ne codent pour aucune pro-téine. En revanche, lemécanisme de réplication du génome,intégralement tributaire desARNpolymérasesADNdépen-dantes eucaryotes, est relativement similaire au mécanismeretrouvé chez certains viroïdes, comme les Avsunviroïdes[16]. Contrairement au HDV, les viroïdes de plantes nes’assemblent pas en virions et se transmettent d’une planteà une autre par les graines ou des blessures, et aux cellulesvoisines au sein d’une plante infectée via les plasmodesmes[18]. Jusqu’à ce jour, aucune transmission active de cel-lule à cellule n’a été observée pour le HDV. Malgré tout,ces similitudes suggèrent que le HDV et les viroïdes pour-raient descendre d’un même ancêtre commun, ou que l’unsoit le précurseur de l’autre. L’hypothèse que le HDV pro-vienne d’un viroïde ayant acquis une séquence codante lorsde son évolution a été proposée en 1996 après la décou-verte dans le génome humain d’un gène codant pour uneprotéine interagissant avec l’antigène du virus (DIPA pourdelta­interacting protein A) et présentant 60 % de simila-rité avec la séquence de la protéine virale [19]. De cettedécouverte, Brazas et Ganem ont émis l’hypothèse quele HDV dérive d’un ARN semblable à un viroïde ayantcapturé la séquence codant pour la protéine DIPA à par-tir de l’ARNm cellulaire. D’autres travaux suggèrent quele HDV pourrait dériver d’un ARN cellulaire. Il y a unedizaine d’années, une étude démontra la présence d’uneactivité ribozyme dans la séquence de l’ARNm codant pourla cytoplasmic polyadenylation element­binding protein 3

(CPEB3) [20]. Ce ribozyme se trouve dans un intron del’ARNm de CPEB3 et s’apparente au ribozyme du HDVpar sa structure et son activité biochimique. Le fait que ce

ribozyme ne soit présent que chez lesmammifères a conduitles auteurs à émettre l’hypothèse que le génome du HDVpourrait dériver du transcriptome humain. L’un des argu-ments repose sur la mise en évidence des ARNs cellulairescirculaires (cARN) décrits dès le début des années 90 [21].Ces cARN sont abondants et interviennent dans différentsprocessus de régulation, comme la prolifération cellulaireet la progression cancéreuse, et interagissent notammentavec desmicroARN. Chaque cARNpeut interagir avec plu-sieurs copies d’un même microARN et jouer ainsi un rôled’« éponge » à microARN [22-24]. Toutefois, les cARNactuellement décrits ne comportent ni la séquence pouvantcoder pour AgHD, ni l’activité ribozyme. De plus, la trèsrécente description d’un virus partageant de nombreusessimilarités avec le HDV chez les oiseaux, mais ne semblantpas dépendre d’un hépadnavirus pour l’achèvement de soncycle viral infirme l’hypothèse d’un HDV exclusivementhumain [25].

Cycle viral du HDV

Les virions HDV et HBV partagent les mêmes protéinesd’enveloppe ; aussi, le mécanisme d’entrée dans les hépa-tocytes est supposé identique pour les deux virus. Lecycle viral est initié par l’attachement de la particulevirale à la surface des hépatocytes via son interactionavec les chaînes de sucres des protéoglycanes à hépa-rane sulfate (HSPG) [26], dont GPC5 [27] (figure 2).Il se lie ensuite de manière spécifique à son récep-teur hépatocytaire, le transporteur d’acides biliaires NTCP(sodium­taurocholate co­transporting polypeptide), indui-sant l’entrée du virus dans la cellule [28]. Les 75 résidusmyristoylés en N-terminal du domaine pré-S1 de la grandeprotéine d’enveloppe du HBV interagissent avec NTCP,potentiellement au niveau du site de liaison des acidesbiliaires [29, 30]. Un autre domaine du transporteur estimpliqué dans l’entrée du virusmais sans interaction directeavec l’enveloppe virale, sa fonction dans l’entrée restantinconnue [28]. La liaison à NTCP induit l’endocytose dela particule virale selon un mécanisme encore inconnu. Letransport de la RNP du HDV du cytoplasme vers le noyauest également peu documenté, mais un signal NLS (signalde localisation nucléaire) a été identifié et caractérisé dansles deux formes d’AgHD [31].Le génome du HDV ne codant pour aucune protéinenon structurale, la réplication virale et la transcription del’ARNm sont entièrement dépendantes des polymérasescellulaires. Le génome sert de matrice pour la transcrip-tion d’ARNm du HDV par l’ARN polymérase II. Unepremière forme d’ARNm est exportée dans le cytoplasmepermettant la production de la forme courte S-AgHD. Laprotéine S-AgHD est importée dans le noyau et stimulela réplication virale [32], au cours de laquelle le génome

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ADNccc du HBV

Genome du HBV intégré

ARNm HBV

AgHBs

L-AgHD

S-AgHD10

11

ARNm AgHD

ARNm AgHD édité

Cytoplasme

Nucléole

Nucléoplasme

Prén

ylation

NTCP HSPG (GPC5)

AAAAA

AAAAA

AAAAA AAAAA

AAAAA

ADAR1

Myrcludex B NAPs

Lonafarnib

NAPs?

1

3

4

5

2

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9

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Figure 2. Cycle viral du HDV. (1) Le cycle viral débute par l’attachement aux protéoglycanes à sulfate d’héparane (HSPG), dont Glypican 5(GPC5) à la surface des hépatocytes. La région pré­S1 de L­AgHBs se lie ensuite au récepteur spécifique du HBV et du HDV, le transporteurd’acides biliaires, NTCP. La particule virale est endocytée et la RNP virale est libérée dans le cytoplasme. (2) Elle est ensuite acheminéeau noyau grâce au signal de localisation nucléaire présent sur les AgHD. (3) L’ARN polymerase II transcrit l’ARNm AgHD qui est ensuiteexporté dans le cytoplasme où il est traduit pour produire la forme courte « Small » de AgHD (S­AgHD). (4) L’ARN polymerase II synthétisel’ARN antigénomique du HDV qui est ensuite transféré dans le nucléole. (5) Dans le nucléole, l’ARN antigénomique sert de matrice pour lanéosynthèse d’ARN génomique par un mécanisme de cercle roulant. (6) L’ARN antigénomique est édité par l’action de l’enzyme ADAR1,supprimant le codon stop de l’ORF S­AgHD. (7) L’ARN antigénomique édité est transcrit en ARN génomique, induisant la synthèse del’ARNm édité plus long. Ce dernier est exporté dans le cytoplasme où il est traduit en forme longue « Large » de AgHD (L­AgHD). (8) L­AgHDcontient un site de prénylation qui est farnésylé par une farnésyltransférase cellulaire avant d’être transféré dans le noyau. (9) Les deuxformes de AgHD interagissent avec les ARN génomiques néo­synthétisés afin de former de nouvelles ribonucléoprotéines virales qui sontexportées dans le cytoplasme. (10) Les ribonucléoprotéines virales interagissent, via une cystéine farnésylée de L­AgHD, avec la partiecytosolique de l’enveloppe du HBV au niveau du réticulum endoplasmique permettant leur enveloppement. (11) Les virions néoforméssont excrétés de la cellule infectée. Les différents antiviraux sont indiqués en rouge. L’hépatocyte représenté est également infecté par leHBV, indiqué par la présence l’ADNccc ou de son génome intégré (cycle complet non représenté).

du HDV recrute l’ARN polymérase II pour la synthèsede multimères d’ARN antigénomique par un mécanismeen cercle roulant [4]. L’activité ribozyme de l’antigénomecatalyse l’auto-clivage des multimères en monomères, quisont ensuite circularisés. L’ARN antigénomique du HDVsert ensuite de matrice à la synthèse de nouvelles copiesde génome du HDV, également selon un mécanisme encercle roulant via l’ARN polymérase II [4]. Bien que laréplication du HDV soit majoritairement portée par l’ARNpolymérase II, plusieurs études suggèrent une implicationdes ARN polymérases I et III dans la synthèse de l’ARN

antigénomique [33, 34]. Il est généralement admis quela transcription des ARN génomiques et antigénomiquesa lieu dans deux compartiments nucléaires différents. Latranscription de l’ARN génomique a lieu dans le nucléo-plasme et celle de l’ARN antigénomique se déroule dans lenucléole [35]. Durant la phase tardive de réplication, l’ARNantigénomique du HDV est édité via l’enzyme ADAR1(adenosine deaminase acting on RNA 1), une adénosine ducodon stop de S-AgHD étant transformée en inosine [4] cequi conduira après réplication au remplacement du codonstop en codon tryptophane (figure 2). La nouvelle version

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des ARN génomiques produits sert alors de matrice pour latranscription d’ARNm codant pour une forme plus longue,L-AgHD. Cette allongement C-terminale de 19 acides ami-nés contient notamment un signal d’export nucléaire (NES)[36] et un site de prénylation sur la cystéine 211 qui estfarnésylée via une farnésyltransférase cellulaire après tra-duction [37, 38]. L-AgHD farnésylé est transféré dansle noyau et inhibe la réplication virale, ce qui a pourconséquence d’orienter le cycle viral vers l’assemblagede nouveaux virions [39]. L’ARN génomique néoformés’associe avec S-AgHD et L-AgHD afin de former de nou-velles RNP qui sont ensuite exportées du noyau, grâce auNES de L-AgHD, par la voie TAP/Aly [40]. La cystéine far-nésylée de L-AgHD permet l’interaction des RNP viralesavec la partie cytosolique de AgHBs à la membrane du réti-culum endoplasmique. L’interaction entre la RNP virale etAgHBs induit l’enveloppement des nouveaux virions ainsique leur sécrétion, selon des voies encore inconnues [41].HDV est donc tributaire de l’expression d’AgHBs pourachever son cycle viral. Au sein d’un hépatocyte préala-blement infecté par le HBV, AgHBs peut être exprimé àpartir de l’ADNccc du HBV mais aussi d’une version inté-grée du génome viral dans le génome de la cellule hôte(figure 2). La réplication active du HBV ne semble en effetpas indispensable à la production de virions HDV [42].Si les grandes étapes du cycle sont à présent bien décrites,de nombreuses zones d’ombre persistent quant aux interac-tions moléculaires entre HDV et facteurs hépatiques dontle virus dépend fortement pour l’achèvement de son cycleréplicatif.

Interactions virus­hôte

Comme le démontre la réplication de son génome, entiè-rement réalisée via les ARN polymérases, le HDV estextrêmement dépendant des facteurs des cellules hôtes pourl’accomplissement de son cycle réplicatif. Même si cesinteractions sont encore largement méconnues, un certainnombre d’acteurs cellulaires ont été décrits. Récemment,un criblage génomique a montré la forte dépendance duHDVà la biosynthèse des pyrimidines. En effet, l’inhibitionde l’enzyme CAD (pour Carbamyl­phosphate synthase

II / Aspartate carbamoyltransférase / Dihydroorotase),qui catalyse les trois premières étapes de la synthèse del’uridine, inhibe fortement la réplication du HDV in vitro,sans impacter la réplication du HBV dans le laps de tempsde l’étude [43]. De plus, l’inhibition du récepteur alphades œstrogènes (ESR1), qui régule l’expression de CAD,inhibe également la réplication virale. En plus de la syn-thèse des pyrimidines, les résultats du criblage suggèrentl’importance d’autres facteurs cellulaires dans l’infectionHDV, notamment des gènes impliqués dans la résistanceà l’insuline ou la voie de signalisation HIF-1 (hypoxia­

inducible factor). À ce jour, il est décrit que l’AgHDinteragit avec plus d’une centaine de protéines, dont beau-coup sont impliquées dans le métabolisme de l’ARN, maiségalement des hélicases à ARN, l’histone H1, ou encoredes sous-unités de l’ARN polymerase II [44]. Les ARNsdu HDV se lient également avec des protéines cellulaires,notamment la protéine kinase R ou ADAR1, qui cata-lyse l’édition de l’ARN antigénomique [45-47]. Au niveaudes senseurs de l’immunité innée, le génome du HDV estdétecté par l’hélicase MDA5 (melanoma differenciation

associated gene 5), induisant la production d’IFN de type Iet III [48]. La production d’ISG (interferon stimulated gene)n’a cependant que peu d’effet sur la réplication duHDV, quiinhibe activement les voies de signalisation de la réponseimmunitaire innée en inhibant la phosphorylation de STAT1(signal transducer and activator of transcription 1) etSTAT2, et par conséquent l’expression des ISG [49]. Enrevanche, L-AgHD induit l’activation de NF-kB (nuclear

factor kappa B) et de STAT3 via le stress oxydatif [50].L’activationde ces facteurs de transcriptionparticipe à l’étatinflammatoire hépatique et pourrait expliquer l’aggravationet l’accélération de la maladie hépatique chez le patient.Par ailleurs, l’infection par le HDV induit chez les patientsune réponse immunitaire adaptative soutenue. En effet, uneétude menée sur des patients atteints d’hépatite virale HBV,HBV/HDV ou virus de l’hépatite C (HCV pour hepatitis C

virus) a montré que les patients HDV présentent les taux lesplus élevés de lymphocytes T CD4+ perforine-positifs [51].Ces lymphocytes éliminent les cellules infectées et jouentprobablement un rôle dans la progression plus rapide de lamaladie hépatique chez les patientsHDV. L’infection induitégalement une réponse immunitaire via les lymphocytes TCD8+ [52], mais un échappement viral par mutations estobservé chez les patients, limitant le contrôle de l’infection.Ces lymphocytes T CD8+ reconnaissant des épitopes duHDV sont retrouvés à la fois chez les patients chroniqueset chez les patients ayant résolu l’infection, suggérant queces mutations pourraient expliquer au moins en partie lamise en place d’une infection chronique, les mutants HDVéchappant au contrôle des cellules T CD8+ [52].

Importance clinique

Histoire naturelle

Chez le patient, il existe deux types d’infection par leHDV : 1) la co-infection initiale simultanée d’un patientsain par le HBV et le HDV, qui évolue chez la majorité desadultes vers l’élimination spontanée des virus (> 95 % descas), comme lors d’une mono-infection HBV [53], aveccependant un risque accru d’hépatite fulminante [54, 55] ;2) la surinfection HDV chez un patient HBC, qui évoluemajoritairement vers une infection persistante et une

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hépatite D chronique (environ 80 % des cas), caractériséepar une inflammation et une fibrose hépatiques progressantavec un risque trois fois plus élevé vers la cirrhose que chezles patients HBC [53, 56]. De plus, le risque de survenued’un carcinome hépatocellulaire est trois fois plus élevéque pour des patients HBC [57]. En comparaison desautres hépatites chroniques, l’hépatite D est marquée parune progression rapide vers la cirrhose, et un risque demortalité plus élevé [4].

Diagnostic

Actuellement, il existe trois méthodes de détection duHDV mais ces méthodes restent inégalement disponibleset de fiabilité variable. Lors de l’infection aiguë, le HDVexprime et sécrète fortement AgHD qui peut être détectépar ELISA. Cependant, ce test n’est réalisable que lorsdes deux premières semaines d’infection, l’AgHD n’étantensuite exprimé que de manière transitoire [58, 59].La seconde méthode consiste à détecter les anticorpsanti-HDV [60]. Les IgM sont les premières produites,concomitamment aux IgM anti-HBc (anti-HBV core pro­

tein) dans le cas d’une co-infection. Les IgG anti-HDVproduites ensuite persistent dans le sérum des patients, quel’infection aiguë ait été résolue ouqu’elle soit devenue chro-nique. Chez les patients positifs pour AgHBs, la détectiondes IgG et IgM (Ig totaux) anti-HDV est généralement lapremière phase de diagnostic d’une infectionHDV,même sile risque de faux-négatifs existe [10]. De plus, la détectiond’IgG anti-HDV ne permet actuellement pas de conclureà une réplication active du virus, les IgG persistant en casd’infection résolue spontanément. Une nouvelle méthoderécemment développée, Q-MAC (quantitative microarray

antibody capture), en plus d’être largement plus sensibleet spécifique que les précédentes, permettrait, en fonctionde l’intensité du signal, de discriminer les patients présen-tant ou non une activité réplicative du HDV, même si cetest nécessite encore des études sur des cohortes plus larges[61, 62].La troisième méthode consiste à détecter l’ARN viral duHDV dans le sérum des patients par qRT-PCR, seul mar-queur d’une réplication active duHDVdans les hépatocytes.La détection de l’ARN viral, après détection des Ig totauxanti-HDV, dans le sérum permet de distinguer une infec-tion aiguë résolue, d’une infection chronique. Cependant,les différents tests disponibles en fonction des pays n’ontpas la même sensibilité ni la même précision dans la déter-mination de la charge virale. De plus, le HDV ayant uneforte variabilité génétique, les tests ne détectent pas effi-cacement les 8 génotypes viraux [63, 64]. L’Organisationmondiale de la santé (OMS) a récemment mis en placeun ARN standard international afin de permettre aux labo-ratoires d’exprimer leurs résultats en unité internationale

(UI). Depuis, plusieurs kits de détection de la charge viraleont été développés permettant une meilleure détection detous les génotypes ainsi qu’une meilleure reproductibilité.L’un de ces kits, l’Eurobioplex HDV kit, a montré sur deséchantillons de patients une forte sensibilité, précision etreproductibilité, dans la détection de tous les génotypes duHDV [65]. Une mesure précise de la charge virale du HDVchez les patients est nécessaire car elle est le seul moyende mesurer et d’analyser la réplication virale afin de suivrel’efficacité des traitements antiviraux.

Traitements actuels

Les méthodes de détection du HDV et le suivi des patientsévoluent mais les traitements actuels reposent toujours surl’utilisation de l’interféron-alpha pégylé (PEG-IFNa), peuspécifique et responsable d’effets secondaires marqués telsqu’état grippal, anémie, dépression, conduisant parfois à unarrêt anticipé du traitement. Les réponses au traitement, del’ordre de 30 %, sont partielles et conduisent rarement àl’élimination persistante de la charge virale [66-68]. Il està noter que les analogues de nucléo(s)tides (NUC) utilisésdans le traitement contre le HBV sont inefficaces contrele HDV [12]. Plusieurs éléments peuvent expliquer la dif-ficulté de traitement du HDV. Premièrement, le HDV necode pour aucune enzyme dans son génome dont la fonc-tion pourrait être ciblée par un traitement antiviral direct. Sile ribozyme du génome présente bien une activité enzyma-tique, les tentatives d’utilisation d’inhibiteurs de ribozymese sont heurtées à une très forte toxicité in vitro, limitant leurcaractérisation antivirale [69]. Par ailleurs, en plus d’uneforte diminution de la réplication du HDV, il est nécessaired’inhiber l’expression d’AgHBs, responsable du rebond decharge virale HDV après arrêt du traitement PEG-IFNa,même si le sujet a développé une réponse virologique soute-nue [70].Cette inhibition n’est cependant observée que chezune minorité de patients à l’aide des traitements PEG-IFNa

actuels (10 % environ) [70].Par conséquent, de nouvelles stratégies de traitement duHDV sont attendues. Dans ce contexte, les moléculesciblant les facteurs hépatiques peuvent être de nouvellesarmes antivirales, dont l’efficacité a été démontrée pourd’autres virus hépatiques [71-73]. Ce type de stratégienécessite toutefois une connaissance approfondie des cyclesviraux et des interactions moléculaires entre virus et fac-teurs cellulaires.

Perspectives thérapeutiques :molécules ciblant l’hôte

Actuellement, plusieurs traitements sont en phase avancéed’essai clinique (tableau 1). Ils ciblent différentes étapes

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du cycle viral à savoir : l’entrée virale, l’assemblage desparticules virales et la sécrétion d’AgHBs.

Inhibiteur de l’entrée virale :

l’exemple du Myrcludex B

LeHBV et le HDV utilisent la même enveloppe virale et, dece fait, le même récepteur, NTCP [74]. Ce récepteur spéci-fique du foie, a rapidement été considéré comme une ciblethérapeutique d’intérêt après la découverte de son rôle dansl’entrée des deux virus (pour des revues, voir [74, 75]). Side nombreux inhibiteurs de NTCP décrits ont montré uneactivité antivirale prometteuse, c’est un lipopeptide dérivéde la partie pré-S1 de l’enveloppe du HBV qui concentrel’essentiel des attentions. Même avant la découverte durécepteur, ce peptide était connu pour son activité préven-tive in vivo, inhibant l’infection par le HBV et le HDV dansun modèle murin [76]. Le peptide pré-S1, site de liaison del’enveloppe virale au récepteur, se fixe spécifiquement surNTCP [77-79]. La forme commerciale du peptide, le Myr-cludex B, peptide myristoylé dérivant des 47 acides aminésenN-terminal du domaine pré-S1 d’AgHBs, a été testé pourson activité antivirale dans de nombreux modèles in vitro etin vivo et en essai clinique [80]. Dans cet essai, 24 patientsHDV co-infectés HBV ont été divisés en trois groupesafin de recevoir, pendant 24 semaines, des injections sous-cutanées quotidiennes de 2 mg de Myrcludex B, couplé ounon au Peg-IFNa, comparé à un traitement Peg-IFNa seul.Le critère principal de l’étude reposait sur lamesure du tauxd’AgHBs. Aucune baisse significative d’AgHBs n’a étéobservée chez les patients après traitement. Toutefois, dansle groupe de patients traités uniquement avecMyrcludex B,6 patients (75%) ont montré une stabilisation des ALT (ala-nine aminotransférase) et 4 patients (50 %) ont montré unebaisse de l’ARN HDV sérique de plus d’un log. De plus,l’élimination du virus a été atteinte chez 2 patients (25 %).Le groupe traité avecMyrcludex B en combinaison au Peg-IFNa a montré de meilleurs résultats avec l’ARN HDVdevenu indétectable chez 5 patients (62,5 %), en revanchel’ARN HDV est réapparu chez tous les patients après arrêtdu traitement, quel que soit le traitement administré [81].Plus récemment, les résultats d’un essai multicentriqueouvert de phase II ont été rendus publics [82]. Cet essai, réa-lisé sur une cohorte de 120 patients co-infectés HBV/HDV,avait pour but de déterminer la tolérance et l’efficacité d’untraitement composé de différentes doses de Myrcludex Ben combinaison avec du ténofovir, un inhibiteur de la trans-criptase inverse duHBV[83]. Les patients, divisés en quatregroupes, ont recu quotidiennement 2, 5 ou 10 mg de Myr-cludexBpar injection sous-cutanée en combinaison avec duténofovir (245 mg/jour), comparé à un traitement au téno-fovir seul pendant 24 semaines. Après cette phase, tous lespatients ont ensuite suivi un traitement au ténofovir pen-

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dant 24 semaines. Le critère principal était une diminutionde l’ARNHDVde 2 log ou une absence d’ARN viral détec-table. À la fin du traitement, l’ARN HDV avait diminué enmoyenne entre 1,6 et 2,7 log, la plus forte dose de Myrclu-dex B étant reliée à la baisse d’ARN HDV la plus forte. Unsuivi à 12 semaines sur une partie des patients a révélé larechute de l’infection chez 60%à83%des patients en fonc-tion des groupes. Plus récemment, les résultats provisoiresde l’étude de phase IIMYR203 indiquent des niveaux indé-tectables de HDV chez 9 des 15 patients traités 48 semainesavec une dose quotidienne de Myrcludex B (2 mg) encombinaison avec le PEG-IFNa [84]. Probablement insuffi-sant en monothérapie, l’utilisation du Myrcludex B sembledonc bénéfique chez les patients HDV en combinaison avecdu ténofovir ou du PEG-IFNa. Cependant, quelques effetssecondaires ont été enregistrés (démangeaisons, augmen-tation des acides sériques, etc.) et les questions en suspensrestent la sécurité et la tolérance à long terme, notammentchez les patients cirrhotiques.

Inhibiteur de l’assemblage : lonafarnib

Durant le cycle viral du HDV, la protéine L-AgHDest farnésylée et cette étape précède l’interaction avecAgHBs. L’inhibition de la farnésylation de L-AgHDinhibe l’assemblage des nouvelles particules virales dansdes modèles cellulaires et murins [85, 86]. Le lonafarnibest un inhibiteur de farnésylation qui a d’abord été testécomme anti-cancéreux et ayant des effets bénéfiques chezles patients atteints du syndrome de Hutchinson-Gilford(progéria) [87]. Bien que son efficacité n’ait pas étédémontrée dans ce contexte, les premières études ontfourni des données de tolérance chez le patient. Un premieressai chez des patients HDV a été réalisé durant lequeldeux doses de lonafarnib (100 mg et 200 mg) ont étéadministrées deux fois par jour par voie orale pendant28 jours. Comparés à un placebo, les deux groupes depatients ont montré une baisse significative de l’ARNHDV (0,73 log pour le groupe 100 mg ; 1,54 log pourle groupe 200 mg). En revanche, le traitement n’a induitaucune baisse ni des ALT, ni des AgHBs, et le taux d’ARNHDV est revenu à la normale chez la totalité des patients àla fin de la période de suivi. De plus, tous les patients ayantrecu la plus forte dose de lonafarnib ont subi de forts effetssecondaires tels que des diarrhées, des nausées et une pertede poids [88]. Afin d’améliorer l’absorption dans le sang delonafarnib et diminuer les effets secondaires, quatre étudesde phases II appelées LOWR-HDV ont été réalisées avecun traitement lonafarnib en combinaison avec le ritonavir,un inhibiteur du cytochrome P450-3A4 qui est le principalacteur dumétabolisme du lonafarnib et améliore sa stabilitésans effet antiviral direct [89]. De manière générale, cesétudes ont montré que la combinaison des deux traitements

permet de diminuer la dose de lonafarnib administréequotidiennement et d’améliorer la tolérance chez le patient[90, 91]. Cette combinaison de traitement a une meilleureefficacité sur la diminution de l’ARN HDVmais cette fortebaisse est en général observée pour la moitié des patientsseulement, et aucune information sur le suivi de cespatients après arrêt du traitement n’est encore disponible.

Les polymères d’acides nucléiques

Les polymères d’acides nucléiques (NAP) sont des oligo-nucléotides phosphorothioés leur conférant une résistanceà la dégradation et à la dénaturation in vivo. Ils possèdentune activité inhibitrice à large spectre contre plusieurs viruscomme le HCV [92] ou le virus herpes simplex [93]. Bienque leur mécanisme d’action précis ne soit pas connu avecprécision, différents NAPs inhibent l’entrée des particulesHDV in vitro [94]. De plus, les NAPs semblent inhiber lasécrétion d’AgHBs, affectant potentiellement le cycle duHDV via divers mécanismes [95]. Leur activité est indé-pendante de leur séquence mais dépendante de leur taille etde leur hydrophobicité [95]. La première étude in vivo a étéconduite chez des canards infectés par le HBV du canard(DHBV) et traités pendant 28 jours avec le NAP REP2055.L’étude a montré une baisse d’AgHBs dans le sérum et del’ADN DHBV, jusqu’à 16 semaines post-traitement, ainsiqu’une augmentation des anticorps anti-DHBV [96]. Latolérance et l’efficacité de REP2055 ainsi que de REP2139,un dérivé de REP2055, ont été étudiées dans une étudeportant sur des patients HBV positifs à AgHBe. Pour cha-cun des composés, le traitement en monothérapie a montréune baisse de AgHBs dans le sérum de 2 à 7 log et del’ADN HBV de 3 à 9 log. De plus, les traitements ont étéaccompagnés d’une production d’anticorps anti-HBs [97].Le NAP REP2139 ayant montré une meilleure tolérancechez les patients ainsi qu’une forte efficacité, il a ensuiteété utilisé dans une nouvelle étude afin d’évaluer sa tolé-rance et son efficacité en co-traitement avec Peg-IFNa surdes patients co-infectés avec HBV et HDV. Les patientsont été injectés une fois par semaine par voie intraveineuseavec 500 mg de REP2139-Ca seul pendant 15 semaines. Letraitement a été suivi par 15 semaines de traitement avec250 mg de REP2139-Ca combiné à 180 mg de Peg-IFNa

puis 33 semaines de traitement avec 180 mg de Peg-IFNa

seul [98]. Après traitement, les patients ont été suivis pen-dant deux ans et l’ARN HDV est resté indétectable chez7 patients (64 %), avec les AgHBs et l’ADN HBV en-dessous du seuil de détection chez 4 (36 %) et 6 (54 %)patients, respectivement [99]. Les résultats obtenus lors deces études sont pour l’instant les plus convaincants, cepen-dant les cohortes étudiées restent de petite taille et les effetsrestent à confirmer sur de plus grandes populations.De plus,le mode d’administration n’est pas adapté à un traitement

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de longue durée. De nouvelles études seront menées afinde tester la tolérance du traitement en administration sous-cutanée. Enfin, le traitement au Peg-IFNa a induit chez5patients une forte augmentation desALT [99]. Les patientsde l’étude étant non-cirrhotiques, cette augmentation estrestée asymptomatique et s’est résolue après arrêt du trai-tement. Le traitement pourrait cependant être plus délétèrechez des patients cirrhotiques.

Conclusion

L’hépatite D reste aujourd’hui incurable et représente unemenace de santé publique majeure pour des millions depatients à travers le monde. Les données épidémiologiquesactuelles sont des estimations approximatives car la pré-sence du HDV chez les patients HBV est encore troppeu souvent recherchée dans certains pays. En plus d’unemeilleure détection, les traitements nécessitent égalementd’être améliorés. Les avancées récentes sur le cycle viral ontpermis l’émergence de nouvelles solutions thérapeutiquesqui démontrent l’intérêt des molécules ciblant l’hôte dansle traitement contre ce virus. La caractérisation exhaustivedes facteurs hépatocytaires impliqués dans le cycle viralpermettra à terme le développement de nouvelles solutionsthérapeutiques pour l’éradication de ce virus hépatiquemajeur.

Remerciements. Les travaux de l’unité résumés dans cetterevue ont notamment été financés par l’Agence nationale dela recherche sur le sida et les hépatites virales (ANRS).Cetterevue est écrite dans le cadre du LabEx HepSYS (ANR-10-LAB-28). Vincent Turon-Lagot bénéficie d’un contratdoctoral (MRES) duministère de l’Enseignement supérieuret de la Recherche.Figures : certains éléments de figure ont été reproduitsou modifiés avec l’autorisation de Servier Medical Art(licence : https://creativecommons.org/licenses/by/3.0/fr/).

Liens d’intérêt :les auteurs déclarent n’avoir aucun liend’intérêt en rapport avec l’article.

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