Laboratoire Of Virologie Moleculaire

Paris, France

Laboratoire Of Virologie Moleculaire

Paris, France
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Zeisel M.B.,French Institute of Health and Medical Research | Zeisel M.B.,University of Strasbourg | Lucifora J.,University of Lyon | Mason W.S.,Fox Chase Cancer Center | And 26 more authors.
Gut | Year: 2015

HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis 'HBV Cure' programme, a scientific workshop was held in Paris in June 2014 to define the state-ofthe- art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection.


Khenchouche A.,Ferhat Abbas University Setif | Sadouki N.,Institute Pasteur dAlgerie | Boudriche A.,Service de Gynecologie | Houali K.,Mouloud Mammeri University | And 2 more authors.
Virology Journal | Year: 2013

Background: Despite the fact that the implication of human papillomavirus (HPV) in the carcinogenesis and prognosis of cervical cancer is well established, the impact of a co-infection with high risk HPV (HR-HPV) and Epstein-Barr virus (EBV) is still not fully understood. Methods. Fifty eight randomly selected cases of squamous cell carcinomas (SCC) of the uterine cervix, 14 normal cervices specimens, 21 CIN-2/3 and 16 CIN-1 cases were examined for EBV and HPV infections. Detection of HR-HPV specific sequences was carried out by PCR amplification using consensus primers of Manos and by Digene Hybrid Capture. The presence of EBV was revealed by amplifying a 660 bp specific EBV sequence of BALF1. mRNA expression of LMP-1 in one hand and protein levels of BARF-1, LMP-1 and EBNA-1 in the other hand were assessed by RT-PCR and immunoblotting and/or immunohischemistry respectively. Results: HR-HPV infection was found in patients with SCC (88%), low-grade (75%) and high grade (95%) lesions compared to only 14% of normal cervix cases. However, 69%, 12.5%, 38.1%, and 14% of SCC, CIN-1, CIN-2/3 and normal cervix tissues, respectively, were EBV infected. The highest co-infection (HR-HPV and EBV) was found in squamous cell carcinoma cases (67%). The latter cases showed 27% and 29% expression of EBV BARF-1 and LMP-1 oncogenes respectively. Conclusion: The high rate of HR-HPV and EBV co-infection in SCC suggests that EBV infection is incriminated in cervical cancer progression. This could be taken into account as bad prognosis in this type of cancer. However, the mode of action in dual infection in cervical oncogenesis needs further investigation. © 2013 Khenchouche et al.; licensee BioMed Central Ltd.


PubMed | Fox Chase Cancer Center, Ecole Normale Superieure de Lyon, National Taiwan University Hospital, French Institute of Health and Medical Research and 10 more.
Type: Journal Article | Journal: Gut | Year: 2015

HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis HBV Cure programme, a scientific workshop was held in Paris in June 2014 to define the state-of-the-art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection.


Verrier E.R.,French Institute of Health and Medical Research | Verrier E.R.,University of Strasbourg | Colpitts C.C.,French Institute of Health and Medical Research | Colpitts C.C.,University of Strasbourg | And 28 more authors.
Hepatology | Year: 2016

Chronic hepatitis B and D infections are major causes of liver disease and hepatocellular carcinoma worldwide. Efficient therapeutic approaches for cure are absent. Sharing the same envelope proteins, hepatitis B virus and hepatitis delta virus use the sodium/taurocholate cotransporting polypeptide (a bile acid transporter) as a receptor to enter hepatocytes. However, the detailed mechanisms of the viral entry process are still poorly understood. Here, we established a high-throughput infectious cell culture model enabling functional genomics of hepatitis delta virus entry and infection. Using a targeted RNA interference entry screen, we identified glypican 5 as a common host cell entry factor for hepatitis B and delta viruses. Conclusion: These findings advance our understanding of virus cell entry and open new avenues for curative therapies. As glypicans have been shown to play a role in the control of cell division and growth regulation, virus-glypican 5 interactions may also play a role in the pathogenesis of virus-induced liver disease and cancer. © 2016 by the American Association for the Study of Liver Diseases.


Verrier E.R.,University of Strasbourg | Colpitts C.C.,University of Strasbourg | Sureau C.,Laboratoire Of Virologie Moleculaire | Baumert T.F.,University of Strasbourg | Baumert T.F.,Institut Universitaire de France
Hepatology International | Year: 2016

Chronic hepatitis B virus (HBV) infection is a leading cause of liver disease worldwide. Virus-induced diseases include cirrhosis, liver failure and hepatocellular carcinoma. Current therapeutic strategies may at best control infection without reaching cure. Complementary antiviral strategies aimed at viral cure are therefore urgently needed. HBV entry is the first step of the infection cycle, which leads to the formation of cccDNA and the establishment of chronic infection. Viral entry may thus represent an attractive target for antiviral therapy. This review summarizes the molecular virology and cell biology of HBV entry, including the discovery and development of new HBV entry inhibitors, and discusses their potential in future treatment of HBV infection. © 2016, Asian Pacific Association for the Study of the Liver.


PubMed | Mount Sinai School of Medicine, University of Birmingham, French Institute of Health and Medical Research, University of Strasbourg and Laboratoire Of Virologie Moleculaire
Type: Journal Article | Journal: Cell reports | Year: 2016

Chronic hepatitis B, C, and D virus (HBV, HCV, and HDV) infections are the leading causes of liver disease and cancer worldwide. Recently, the solute carrier and sodium taurocholate co-transporter NTCP has been identified as a receptor for HBV and HDV. Here, we uncover NTCP as a host factor regulating HCV infection. Using gain- and loss-of-function studies, we show that NTCP mediates HCV infection of hepatocytes and is relevant for cell-to-cell transmission. NTCP regulates HCV infection by augmenting the bile-acid-mediated repression of interferon-stimulated genes (ISGs), including IFITM3. In conclusion, our results uncover NTCP as a mediator of innate antiviral immune responses in the liver, and they establish a role for NTCP in the infection process of multiple viruses via distinct mechanisms. Collectively, our findings suggest a role for solute carriers in the regulation of innate antiviral responses, and they have potential implications for virus-host interactions and antiviral therapies.


PubMed | University of Strasbourg and Laboratoire Of Virologie Moleculaire
Type: Journal Article | Journal: Hepatology international | Year: 2016

Chronic hepatitis B virus (HBV) infection is a leading cause of liver disease worldwide. Virus-induced diseases include cirrhosis, liver failure and hepatocellular carcinoma. Current therapeutic strategies may at best control infection without reaching cure. Complementary antiviral strategies aimed at viral cure are therefore urgently needed. HBV entry is the first step of the infection cycle, which leads to the formation of cccDNA and the establishment of chronic infection. Viral entry may thus represent an attractive target for antiviral therapy. This review summarizes the molecular virology and cell biology of HBV entry, including the discovery and development of new HBV entry inhibitors, and discusses their potential in future treatment of HBV infection.


Sureau C.,Laboratoire Of Virologie Moleculaire | Sureau C.,French National Center for Scientific Research | Salisse J.,Laboratoire Of Virologie Moleculaire
Hepatology | Year: 2013

Two determinants of infectivity have been identified in the hepatitis B virus (HBV) envelope proteins: a pre-S1 receptor-binding site and an uncharacterized determinant in the antigenic loop (AGL), which is structurally related to the antigenic a-determinant. Infection would proceed through virus attachment to cell surface heparan sulfate (HS) proteoglycans (HSPGs) before pre-S1 engages a specific receptor for uptake. Using heparin binding and in vitro infection assays with hepatitis D virus as a surrogate for HBV, we established that HS binding is mediated by the AGL. Electrostatic interaction was shown to depend upon AGL residues R122 and K141, because their substitution with alanine modified the virus net-charge and prevented binding to heparin, attachment to hepatocytes, and infection. In addition to R122 and K141, the HS binding determinant was mapped to cysteines and prolines, which also define the conformational a-determinant. The importance of AGL conformation was further demonstrated by the concomitant loss of a-determinant and heparin binding upon treatment of viral particles with membrane-impermeable reducing agent. Furthermore, envelope proteins extracted from the viral membrane with a nonionic detergent were shown to conserve the a-determinant but to lose heparin affinity/avidity. Conclusion: Our findings support a model in which attachment of HBV to HSPGs is mediated by the AGL HS binding site, including only two positively charged residues (R122 and K141) positioned precisely in a three-dimensional AGL structure that is stabilized by disulfide bonds. HBV envelope proteins would individually bind to HS with low affinity, but upon their clustering in the viral membrane, they would reach sufficient avidity for a stable interaction between virus and cell surface HSPGs. Our data provide new insight into the HBV entry pathway, including the opportunity to design antivirals directed to the AGL-HS interaction. © 2012 American Association for the Study of Liver Diseases.


Li J.,Brown University | Zong L.,Brown University | Zong L.,Fudan University | Sureau C.,Laboratoire Of Virologie Moleculaire | And 4 more authors.
Journal of Virology | Year: 2016

Cell culture (cc)-derived hepatitis B virus (HBV) can infect differentiated HepaRG cells, but efficient infection requires addition of polyethylene glycol (PEG) during inoculation. Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV receptor enabled ccHBV infection of NTCP reconstituted HepG2 cells, although very little hepatitis B surface antigen (HBsAg) is produced. We found infection by patient serum-derived HBV (sHBV), which required purification of viral particles through ultracentrifugation or PEG precipitation, was PEG independent and much more efficient in HepaRG cells than in HepG2/NTCP cells. In contrast to hepatitis B e antigen (HBeAg), HBsAg was not a reliable marker of productive sHBV infection at early time points. A low HBsAg/HBeAg ratio by ccHBV-infected HepG2/NTCP cells was attributable to dimethyl sulfoxide (DMSO) in culture medium, NTCP overexpression, and HBV genotype D. HepG2/NTCP cells released more viral antigens than HepG2 cells after HBV genome delivery by adeno-associated virus, and stable expression of NTCP in a ccHBV producing cell line increased viral mRNAs, proteins, replicative DNA, and covalently closed circular DNA. NTCP protein expression in HepG2/ NTCP cells, despite being driven by the cytomegalovirus promoter, was markedly increased by DMSO treatment. This at least partly explains ability of DMSO to promote ccHBV infection in such cell lines. In conclusion, NTCP appeared inefficient to mediate infection by serum-derived HBV. It could promote HBV RNA transcription while inhibiting HBsAg secretion. Efficient PEG-independent sHBV infection of HepaRG cells permits comparative studies of diverse clinical HBV isolates and will help identify additional factors on virion surface promoting attachment to hepatocytes. © 2016, American Society for Microbiology. All Rights Reserved.


PubMed | University of Buenos Aires, University of Lyon, French Institute of Health and Medical Research, IGBMC and 5 more.
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2015

Chronic hepatitis B and D infections are major causes of liver disease and hepatocellular carcinoma worldwide. Efficient therapeutic approaches for cure are absent. Sharing the same envelope proteins, hepatitis B virus and hepatitis delta virus use the sodium/taurocholate cotransporting polypeptide (a bile acid transporter) as a receptor to enter hepatocytes. However, the detailed mechanisms of the viral entry process are still poorly understood. Here, we established a high-throughput infectious cell culture model enabling functional genomics of hepatitis delta virus entry and infection. Using a targeted RNA interference entry screen, we identified glypican 5 as a common host cell entry factor for hepatitis B and delta viruses.These findings advance our understanding of virus cell entry and open new avenues for curative therapies. As glypicans have been shown to play a role in the control of cell division and growth regulation, virus-glypican 5 interactions may also play a role in the pathogenesis of virus-induced liver disease and cancer.

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