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Molecular Virology of Hepatitis C Virus (HCV): 2006 Update
Brass Volker,Moradpour Darius,Blum Hubert E.
International Journal of Medical Sciences , 2006,
Abstract: Fascinating progress in the understanding of the molecular biology of hepatitis C virus (HCV) was achieved recently. The replicon system revolutionized the investigation of HCV RNA replication and facilitated drug discovery. Novel systems for functional analyses of the HCV glycoproteins allowed the validation of HCV receptor candidates and the investigation of cell entry mechanisms. Most recently, recombinant infectious HCV could be produced in cell culture, rendering all steps of the viral life cycle, including entry and release of viral particles, amenable to systematic analysis. In this review, we summarize recent advances and discuss future research directions.
Entry of hepatitis C virus into the cell: A therapeutic target  [cached]
José Antonio Del Campo,ángela Rojas,Manuel Romero-Gómez
World Journal of Gastroenterology , 2012, DOI: 10.3748/wjg.v18.i33.4481
Abstract: Several receptors have been identified as implicated on viral entry into the hepatocyte; and, this interaction between the virus and potential receptors could modulate infection, spontaneous viral clearance, persistence of the infection and the widespread of the virus as outbreak. Nevertheless, the playing role of each of them remains controversial. The Niemann-Pick type C1 like 1 gene (NPC1L1) receptor has been recently implicated on hepatitis C virus (HCV) entry into the cell and ezetimibe, an anti-cholesterol drug seems to block that, emerging the idea to control hepatitis C outbreak modulating lipid-related receptors. Hepatitis C infection seems to modulate lipid metabolism according to host genetic background. Indeed, it circulates like a lipoviroparticle. The main aim of this field of vision would be to discuss the role of hepatocyte receptors implicated on virus entry, especially NPC1L1 and the therapeutic options derived from the better knowledge about HCV-lipids- receptors interaction.
Study of the early steps of the Hepatitis B Virus life cycle  [cached]
Lu Xuanyong,Block Timothy
International Journal of Medical Sciences , 2004,
Abstract: Hepatitis B virus (HBV) is a human pathogen, causing the serious liver disease. Despite considerable advances in the understanding of the natural history of HBV disease, most of the early steps in the virus life cycle remain unclear. Virus attachment to permissive cells, fusion and penetration through cell membranes and subsequent genome release, are largely a mystery. Current knowledge on the early steps of HBV life cycle has mostly come from molecular cloning, expression of individual genes and studies of the infection of duck hepatitis B virus (DHBV) with duck primary duck hepatocytes. However, considering of the difference of the surface protein of HBV and DHBV both in the composition and sequence, the degree to which information from DHBV applies to human HBV attachment and entry may be limited. A major obstacle to the study HBV infection is the lack of a reliable and sensitive in vitro infection system. We have found that the digestion of HBV and woodchuck hepatitis virus (WHBV) by protease V8 led to the infection of HepG2 cell, a cell line generally is refractory for their infection [Lu et al. J Virol. 1996. 70. 2277-2285. Lu et al. Virus Research. 2001. 73(1): 27-4]. Further studies showed that a serine protease inhibitor Kazal (SPIK) was over expressed in the HepG2 cells. Therefore, it is possible that to silence the over expressed SPIK and thus to reinstate the activity of indispensable cellular proteases can result in the restoration of the susceptibility of HepG2 cells for HBV infection. The establishing a stable cell line for study of the early steps of HBV life cycle by silencing of SPIK is discussed.
A Novel Small Molecule Inhibitor of Hepatitis C Virus Entry  [PDF]
Carl J. Baldick ,Michael J. Wichroski,Annapurna Pendri,Ann W. Walsh,Jie Fang,Charles E. Mazzucco,Kevin A. Pokornowski,Ronald E. Rose,Betsy J. Eggers,Mayla Hsu,Weixu Zhai,Guangzhi Zhai,Samuel W. Gerritz,Michael A. Poss,Nicholas A. Meanwell,Mark I. Cockett,Daniel J. Tenney
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1001086
Abstract: Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 μM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.
Interplay among cellular polarization, lipoprotein metabolism and hepatitis C virus entry  [cached]
Ignacio Benedicto,Francisca Molina-Jiménez,Ricardo Moreno-Otero,Manuel López-Cabrera
World Journal of Gastroenterology , 2011, DOI: 10.3748/wjg.v17.i22.2683
Abstract: Hepatitis C virus (HCV) infects more than three million new individuals worldwide each year. In a high percentage of patients, acute infections become chronic, eventually progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Given the lack of effective prophylactic or therapeutic vaccines, and the limited sustained virological response rates to current therapies, new approaches are needed to prevent, control, and clear HCV infection. Entry into the host cell, being the first step of the viral cycle, is a potential target for the design of new antiviral compounds. Despite the recent discovery of the tight junction-associated proteins claudin-1 and occludin as HCV co-receptors, which is an important step towards the understanding of HCV entry, the precise mechanisms are still largely unknown. In addition, increasing evidence indicates that tools that are broadly employed to study HCV infection do not accurately reflect the real process in terms of viral particle composition and host cell phenotype. Thus, systems that more closely mimic natural infection are urgently required to elucidate the mechanisms of HCV entry, which will in turn help to design antiviral strategies against this part of the infection process.
The CD81 Partner EWI-2wint Inhibits Hepatitis C Virus Entry  [PDF]
Vera Rocha-Perugini, Claire Montpellier, David Delgrange, Czeslaw Wychowski, Fran?ois Helle, André Pillez, Hervé Drobecq, Fran?ois Le Naour, Stéphanie Charrin, Shoshana Levy, Eric Rubinstein, Jean Dubuisson, Laurence Cocquerel
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001866
Abstract: Two to three percent of the world's population is chronically infected with hepatitis C virus (HCV) and thus at risk of developing liver cancer. Although precise mechanisms regulating HCV entry into hepatic cells are still unknown, several cell surface proteins have been identified as entry factors for this virus. Among these molecules, the tetraspanin CD81 is essential for HCV entry. Here, we have identified a partner of CD81, EWI-2wint, which is expressed in several cell lines but not in hepatocytes. Ectopic expression of EWI-2wint in a hepatoma cell line susceptible to HCV infection blocked viral entry by inhibiting the interaction between the HCV envelope glycoproteins and CD81. This finding suggests that, in addition to the presence of specific entry factors in the hepatocytes, the lack of a specific inhibitor can contribute to the hepatotropism of HCV. This is the first example of a pathogen gaining entry into host cells that lack a specific inhibitory factor.
RNA Interference and Single Particle Tracking Analysis of Hepatitis C Virus Endocytosis  [PDF]
Kelly E. Coller,Kristi L. Berger,Nicholas S. Heaton,Jacob D. Cooper,Rosa Yoon,Glenn Randall
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000702
Abstract: Hepatitis C virus (HCV) enters hepatocytes following a complex set of receptor interactions, culminating in internalization via clathrin-mediated endocytosis. However, aside from receptors, little is known about the cellular molecular requirements for infectious HCV entry. Therefore, we analyzed a siRNA library that targets 140 cellular membrane trafficking genes to identify host genes required for infectious HCV production and HCV pseudoparticle entry. This approach identified 16 host cofactors of HCV entry that function primarily in clathrin-mediated endocytosis, including components of the clathrin endocytosis machinery, actin polymerization, receptor internalization and sorting, and endosomal acidification. We next developed single particle tracking analysis of highly infectious fluorescent HCV particles to examine the co-trafficking of HCV virions with cellular cofactors of endocytosis. We observe multiple, sequential interactions of HCV virions with the actin cytoskeleton, including retraction along filopodia, actin nucleation during internalization, and migration of internalized particles along actin stress fibers. HCV co-localizes with clathrin and the ubiquitin ligase c-Cbl prior to internalization. Entering HCV particles are associated with the receptor molecules CD81 and the tight junction protein, claudin-1; however, HCV-claudin-1 interactions were not restricted to Huh-7.5 cell-cell junctions. Surprisingly, HCV internalization generally occurred outside of Huh-7.5 cell-cell junctions, which may reflect the poorly polarized nature of current HCV cell culture models. Following internalization, HCV particles transport with GFP-Rab5a positive endosomes, which is consistent with trafficking to the early endosome. This study presents technical advances for imaging HCV entry, in addition to identifying new host cofactors of HCV infection, some of which may be antiviral targets.
Potential cellular receptors involved in hepatitis C virus entry into cells
Daniel Favre, Beat Muellhaupt
Lipids in Health and Disease , 2005, DOI: 10.1186/1476-511x-4-9
Abstract: Hepatitis C virus (HCV) is a major cause of chronic liver disease, with approximately 170 million people infected worldwide [1]. Infection with HCV can lead to hepatocellular carcinoma [2]. To study the adsorption, penetration and replication of the virus, a major obstacle has been the lack of an efficient and reproducible in vitro infection system. Thus, the identification of the HCV receptor on the surface of susceptible cells, especially hepatocytes, remains a major challenge for the development of both in vitro cell culture systems, and for the design of successful therapies [3,4].Several cellular receptors have been proposed to mediate the entry of HCV into cells, namely the CD81 receptor [5,6], the scavenger receptor class B type I (SR-BI) receptor [7], and the low density lipoprotein (LDL) receptor [8,9].The tetraspanin CD81 (also named TAPA-1) is a widely-expressed cell surface protein of 26 kDa that is involved in pleiotropic activities such as cell adhesion, motility, metastasis, cell activation and signal transduction [10]. It physically associates with a variety of other membrane proteins such as integrins, lineage-specific molecules and other tetraspanins. It is expressed in most human tissues with the exception of the red blood cells and platelets. Association of CD81 with other molecules has been extensively studied with B and T cells.It was shown that the expression of CD81 on nonpermissive human, but not murine, hepatic cells enabled the entry of HCV pseudoviruses. The inhibition of viral entry, achieved by application of anti-CD81 monoclonal antibodies, occurred at a step following viral attachment to target cells [11]. When the HCV envelope glycoproteins E1 and E2 were expressed in a baculovirus system, the purified E1-E2 heterodimer interacted with CD81, as well as with the LDL receptor [12]. The human CD81 protein was expressed in bacteria, and the critical amino acids in CD81 involved in the interaction with the viral envelope protein E2 were i
Recent advances in Hepatitis B vaccination
Madalinski Kazimierz
Hepatitis B Annual , 2008,
Abstract: Hepatitis B virus is a microorganism formed in the excess of surface antigen which is devoid of nucleic acid. Surface antigen of HBV was from the beginning the natural candidate for the vaccine which was thus produced by isolation of plasma HBsAg and later substituted by recombinant protein(s). The Extended Program of Immunization was beneficial for the reduction of HBV incidence in the populations of many participating countries. It is further postulated that HCC incidence in the world was also reduced at least in the portion caused by hepatitis B virus. Persistence of anti-HBV immunity was first measured by quantitative anti-HBs assay determined at 1 month post vaccination cycle, and then at different time points, even up to 12-15 years. The frontier of 10 IU/L (mIU/ml) is a mark of sustained immunity. However, cellular immunity studies revealed that this kind of response is very important in the defense against the virus and may last longer than the detectable antibodies. It was shown that ′full′ surface vaccines, i.e. preS+S, may give stronger immunity and are good even for neonates. The next generation vaccines are DNA-based and plant-based HBV vaccines. This last category raises many hopes and with sufficient immunogenicity could ensure the most comfortable route of administration.
Adaptation of Hepatitis C Virus to Mouse CD81 Permits Infection of Mouse Cells in the Absence of Human Entry Factors  [PDF]
Julia Bitzegeio,Dorothea Bankwitz,Kathrin Hueging,Sibylle Haid,Christiane Brohm,Mirjam B. Zeisel,Eva Herrmann,Marcus Iken,Michael Ott,Thomas F. Baumert,Thomas Pietschmann
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000978
Abstract: Hepatitis C virus (HCV) naturally infects only humans and chimpanzees. The determinants responsible for this narrow species tropism are not well defined. Virus cell entry involves human scavenger receptor class B type I (SR-BI), CD81, claudin-1 and occludin. Among these, at least CD81 and occludin are utilized in a highly species-specific fashion, thus contributing to the narrow host range of HCV. We adapted HCV to mouse CD81 and identified three envelope glycoprotein mutations which together enhance infection of cells with mouse or other rodent receptors approximately 100-fold. These mutations enhanced interaction with human CD81 and increased exposure of the binding site for CD81 on the surface of virus particles. These changes were accompanied by augmented susceptibility of adapted HCV to neutralization by E2-specific antibodies indicative of major conformational changes of virus-resident E1/E2-complexes. Neutralization with CD81, SR-BI- and claudin-1-specific antibodies and knock down of occludin expression by siRNAs indicate that the adapted virus remains dependent on these host factors but apparently utilizes CD81, SR-BI and occludin with increased efficiency. Importantly, adapted E1/E2 complexes mediate HCV cell entry into mouse cells in the absence of human entry factors. These results further our knowledge of HCV receptor interactions and indicate that three glycoprotein mutations are sufficient to overcome the species-specific restriction of HCV cell entry into mouse cells. Moreover, these findings should contribute to the development of an immunocompetent small animal model fully permissive to HCV.
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