165 research outputs found
Non-Coding RNAs and Hepatitis C Virus-Induced Hepatocellular Carcinoma
No full textHepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Despite recent improvements, effective treatments for HCC are still missing and new tools for early detection are needed. Non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression and key players in human carcinogenesis, including HCC. Aberrant expression of ncRNAs is associated with HCC metastasis, invasion, dissemination, and recurrence. This review will focus on the recent advances in ncRNA expression profiles, their dysregulation in HCV-related HCC, and the clinical perspective of ncRNA signatures for the early detection of HCC
Host Epigenetic Alterations and Hepatitis B Virus-Associated Hepatocellular Carcinoma
No full textHepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and a leading cause of cancer-related deaths worldwide. Although much progress has been made in HCC drug development in recent years, treatment options remain limited. The major cause of HCC is chronic hepatitis B virus (HBV) infection. Despite the existence of a vaccine, more than 250 million individuals are chronically infected by HBV. Current antiviral therapies can repress viral replication but to date there is no cure for chronic hepatitis B. Of note, inhibition of viral replication reduces but does not eliminate the risk of HCC development. HBV contributes to liver carcinogenesis by direct and indirect effects. This review summarizes the current knowledge of HBV-induced host epigenetic alterations and their association with HCC, with an emphasis on the interactions between HBV proteins and the host cell epigenetic machinery leading to modulation of gene expression
Role of hypervariable region 1 for the interplay of hepatitis C virus with entry factors and lipoproteins
No full textHepatitis C virus (HCV) particles associate with lipoproteins and infect cells by using at least four cell entry factors. These factors include scavenger receptor class B type I (SR-BI), CD81, claudin 1 (CLDN1), and occludin (OCLN). Little is known about specific functions of individual host factors during HCV cell entry and viral domains that mediate interactions with these factors. Hypervariable region 1 (HVR1) within viral envelope protein 2 (E2) is involved in the usage of SR-BI and conceals the viral CD81 binding site. Moreover, deletion of this domain alters the density of virions. We compared lipoprotein interaction, surface attachment, receptor usage, and cell entry between wild-type HCV and a viral mutant lacking this domain. Deletion of HVR1 did not affect CD81, CLDN1, and OCLN usage. However, unlike wild-type HCV, HVR1-deleted viruses were not neutralized by antibodies and small molecules targeting SR-BI. Nevertheless, modulation of SR-BI cell surface expression altered the infection efficiencies of both viruses to similar levels. Analysis of affinity-purified virions revealed comparable levels of apolipoprotein E (ApoE) incorporation into viruses with or without HVR1. However, ApoE incorporated into these viruses was differentially recognized by ApoE-specific antibodies. Thus, SR-BI has at least two functions during cell entry. One of them can be neutralized by SR-BI-targeting molecules, and it is critical only for wild-type HCV. The other one is important for both viruses but apparently is not inactivated by the SR-BI binding antibodies and small molecules evaluated here. In addition, HVR1 modulates the conformation and/or epitope exposure of virus particle-associated ApoE
HCV entry and neutralizing antibodies: lessons from viral variants.
No full textInternational audienceEvaluation of: Grove J, Nielsen S, Zhong J et al.: Identification of a residue in hepatitis C virus E2 glycoprotein that determines scavenger receptor BI and CD81 receptor dependency and sensitivity to neutralizing antibodies. J. Virol. 82 (24), 12020-12029 (2008). Recent data suggest that a strong, early, broad neutralizing antibody response may contribute to the control of HCV in the acute phase of infection. However, the majority of individuals fail to clear HCV during the first months following infection and develop chronic infection despite the presence of anti-HCV antibodies. A prerequisite of the understanding behind the mechanisms of viral escape from antibody-mediated neutralization is the identification of various host-entry factors mediating the first steps of viral infection - binding and entry of HCV is believed to be a multistep process involving HCV envelope glycoproteins E1 and E2 as well as several host-cell surface molecules such as CD81, scavenger receptor class B type I, members of the claudin family and occludin. In this article, Grove et al. describe a single mutation in the HCV envelope glycoprotein E2 that alters glycoprotein structure thereby modulating viral interaction with scavenger receptor class B type I and CD81, and increasing sensitivity to neutralizing antibodies. The results of this study highlight the importance of the characterization of the interplay between HCV particles and host-cell factors for the understanding of virus neutralization by host-immune responses and pathogenesis of HCV infection
Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors
No full textHepatitis 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
Competition through Technical Progress
No full textThe relationship between technical progress and price competition is a controversial issue in economics. This paper highlights the fact that investment in technical progress is an authentic type of competition which benefits the consumers rather than the industry. This type of competition exists when the potential for technical progress, which can be incorporated by firms through investment, is high enough. Competition is, in fact, made up of two components: A static one which is known as price or quantity competition and a dynamic one, the Technical Progress competition which also contribute to reduce prices and increase quantities for consumers. Consequently, the economic factors that increase a firm's margin do not have to be viewed as the consumers' enemy, but rather as an ally, under specific conditions, because they allow higher investments in new technology by which firms increase their capacities and attract higher demand from consumers. This paper also underlines that, for a mature market, the maximum Consumer Surplus as well as Social Welfare are attained by a constant level of combined competition which is only dependent on the size of the market and the number of firms. The level of combined competition can be defined as the product of the static and the dynamic level of competition. As a consequence, the higher the potential of technical progress is, the lower the level of static competition must be in order to reach the maximum level of Consumer Surplus and Social Welfare. --Investment,Competition,Technical Progress,Dynamic Competition
Chiral four-dimensional F-theory compactifications with SU(5) and multiple U(1)-factors
No full textWe develop geometric techniques to determine the spectrum and the chiral indices of matter multiplets for four-dimensional F-theory compactifications on elliptic Calabi-Yau fourfolds with rank two Mordell-Weil group. The general elliptic fiber is the Calabi-Yau onefold in dP 2. We classify its resolved elliptic fibrations over a general base B. The study of singularities of these fibrations leads to explicit matter representations, that we determine both for U(1) × U(1) and SU(5) × U(1) × U(1) constructions. We determine for the first time certain matter curves and surfaces using techniques involving prime ideals. The vertical cohomology ring of these fourfolds is calculated for both cases and general formulas for the Euler numbers are derived. Explicit calculations are presented for a specific base B = P3. We determine the general G 4-flux that belongs to HVV(2,2)of the resolved Calabi-Yau fourfolds. As a by-product, we derive for the first time all conditions on G 4-flux in general F-theory compactifications with a non-holomorphic zero section. These conditions have to be formulated after a circle reduction in terms of Chern-Simons terms on the 3D Coulomb branch and invoke M-theory/F-theory duality. New Chern-Simons terms are generated by Kaluza-Klein states of the circle compactification. We explicitly perform the relevant field theory computations, that yield non-vanishing results precisely for fourfolds with a non-holomorphic zero section. Taking into account the new Chern-Simons terms, all 4D matter chiralities are determined via 3D M-theory/F-theory duality. We independently check these chiralities using the subset of matter surfaces we determined. The presented techniques are general and do not rely on toric data. © 2014 The Author(s)
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