Étude des interactions entre les virus des hépatites B et delta et évaluation de nouveaux immuno-modulateurs anti-HDV dans des modèles cellulaires de surinfection

HDV/HBV superinfection is the most aggressive form of chronic viral hepatitis and is estimated to affect 15-20 million patients worldwide. HDV is not susceptible to available direct anti-HBV drugs and sustained response to IFNα therapy occurs in less than 1/4 of patients. Despite the faster progression of liver disease, most HDV/ HBV infected patients present a suppression of HBV replication. The details of the interactions between HDV, HBV and the host cell innate immune response remain largely unexplored and research efforts have been limited by the lack of infection models. The aims of this thesis work were: i) to study HDV infection and the interplay with the host innate immune response; ii) to identify novel therapeutic strategies for the inhibition of HDV; iii) to further explore HDV/ HBV interference. The experimental strategy was based on infection of dHepaRG cells, which are known to be permissive to both HBV and HDV full replicative cycles and to present physiological innate immune responses. We observed that: i) HDV infection is associated with a strong, yet transient replication, a potent induction of the expression of ISGs; ii) IFN-α treatment of HDVinfected cells does not induce a further increase of ISG expression and has a modest antiviral activity. Conversely, some PRR agonists, in particular those inducing the NFkB pathway, induce a strong decline in HDV replication; iii) despite the low number of coinfected cells, HDV as well as its encoded proteins exert a repressive effect on HBV replication. Our work opens an array of perspectives on the pathogenesis of hepatitis delta and the identification of novel immune modulatory therapeutic strategiesLa surinfection par HDV/ HBV est la forme la plus grave d'hépatite virale chronique et affecte entre 15-20 millions de patients au niveau mondial. HDV n'est pas susceptible aux traitements anti-HBV et le taux de réponse à l'IFNα est <25%. Malgré une progression plus rapide de la maladie hépatique, la majorité des patients présente une suppression de la réplication du HBV. Les détails des interactions entre HDV, HBV et le système immunitaire inné des cellules infectées restent inconnus. Les objectifs de ces travaux de thèse ont été: i) l'étude de l'infection par HDV et son interaction avec la réponse innée cellulaire; ii) l'identification de nouvelles stratégies thérapeutiques anti-HDV; iii) l'exploration de l'interaction entre HDV et HBV. L'approche expérimentale a été basée sur l'infection de cellules dHepaRG, capables d´entretenir des cycles réplicatifs complets de HBV et HDV et ayant une réponse immunitaire innée physiologique. Nous avons observé que: i) l'infection par HDV est associée à un réplication forte dans un nombre limité de cellules, et à une induction de l'expression des ISGs; ii) le traitement des cellules infectées par HDV avec de l'IFNα ne conduit pas à une induction accrue des ISGs et a une faible activité antivirale. Quelques agonistes de PRR, notamment activant la voie NF-kB, induisent une forte diminution de la réplication de HDV; iii) malgré le faible nombre de cellules infectées, HDV et ses protéines induisent une diminution de la réplication de HBV. Ces travaux ouvrent des perspectives importantes concernant la caractérisation de la pathogénèse de l'hépatite delta et l'identification de nouvelles stratégies thérapeutiques immuno modulatrice

[Hepatitis delta: Clinical aspects and therapeutic perspectives]

International audienceHDV prevalence must not be disregarded, as the virus is associated with a higher severity of hepatic disease. All HBV carriers should be tested for HDV as well, at least once during the disease history, and in case of worsening of a chronic HBV hepatitis. Diagnosis should rely on anti-HDV antibody testing, and confirmed by HDV RNA detection and quantification by RT-qPCR. The only treatment available is pegylated alpha interferon. Optimal duration of treatment has not yet been proven, and relapses are common. Disease follow-up should be carried on even when SVR is obtained, in order to track late viral relapses, and fibrosis complications (such as HCC screening

A review on hepatitis D: From virology to new therapies

Hepatitis delta virus (HDV) is a defective virus that requires the hepatitis B virus (HBV) to complete its life cycle in human hepatocytes. HDV virions contain an envelope incorporating HBV surface antigen protein and a ribonucleoprotein containing the viral circular single-stranded RNA genome associated with both forms of hepatitis delta antigen, the only viral encoded protein. Replication is mediated by the host cell DNA-dependent RNA polymerases. HDV infects up to72 million people worldwide and is associated with an increased risk of severe and rapidly progressive liver disease. Pegylated interferon-alpha is still the only available treatment for chronic hepatitis D, with poor tolerance and dismal success rate. Although the development of antivirals inhibiting the viral replication is challenging, as HDV does not possess its own polymerase, several antiviral molecules targeting other steps of the viral life cycle are currently under clinical development: Myrcludex B, which blocks HDV entry into hepatocytes, lonafarnib, a prenylation inhibitor that prevents virion assembly, and finally REP 2139, which is thought to inhibit HBsAg release from hepatocytes and interact with hepatitis delta antigen. This review updates the epidemiology, virology and management of HDV infection. Keywords: Hepatitis delta virus, Virus life cycle, Chronic hepatitis, Epidemiology, Treatment, Hepatitis delta managemen

Sexually transmitted infections knowledge in different populations attending a French university hospital: a prospective observational study

Abstract We conducted a prospective study about sexually transmitted infections (STIs) knowledge in different populations attending Lyon's University Hospitals in order to estimate awareness on STIs. Pre-exposure prophylaxis (PrEP)-users (PrEP group), persons living with HIV (PLWH group) and persons undergoing free STI screening (screening group) filled an anonymous questionnaire evaluating STI knowledge. A composite STI knowledge score was calculated and was correlated with patients’ characteristics. A total of 756 patients were enrolled in three groups: screening ( n = 509), PrEP ( n = 103) and PLWH ( n = 144). STI transmission knowledge was better for HIV than for other STIs. The median STI knowledge score was significantly higher in PrEP-users than in the screening and PLWH groups. PrEP use and a previous STI diagnosis were independently associated with a higher score. PrEP-users have better STI knowledge than PLWH and persons undergoing free STI screening. Sexual health promotion interventions routinely reserved to PrEP-users in France seem to be effective in raising the awareness of this group for STIs. Continuous efforts are justified for PLWH and the younger layers of the population

Chronic hepatitis D and hepatocellular carcinoma: a systematic review and meta-analysis of observational studies

Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis but its role in the development of hepatocellular carcinoma (HCC) remains debated. We conducted a systematic review and meta-analysis of epidemiological studies to examine whether CHD is associated with an increased risk of HCC

Réplication du génome du virus de l’hépatite delta : un rôle pour la petite protéine delta S-HDAg

International audienc

Hepatitis Delta Virus histone mimicry drives the recruitment of chromatin remodelers for viral RNA replication

International audienceHepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication