Showing papers by "Darius Moradpour published in 2002"

Expression of Hepatitis C Virus Proteins Induces Distinct Membrane Alterations Including a Candidate Viral Replication Complex

Abstract: Plus-strand RNA viruses characteristically replicate their genome in association with altered cellular membranes. In the present study, the capacity of hepatitis C virus (HCV) proteins to elicit intracellular membrane alterations was investigated by expressing, in tetracycline-regulated cell lines, a comprehensive panel of HCV proteins individually as well as in the context of the entire HCV polyprotein. As visualized by electron microscopy (EM), expression of the combined structural proteins core-E1-E2-p7, the NS3-4A complex, and protein NS4B induced distinct membrane alterations. By immunogold EM (IEM), the membrane-altering proteins were always found to localize to the respective altered membranes. NS4B, a protein of hitherto unknown function, induced a tight structure, designated membranous web, consisting of vesicles in a membranous matrix. Expression of the entire HCV polyprotein gave rise to membrane budding into rough endoplasmic reticulum vacuoles, to the membranous web, and to tightly associated vesicles often surrounding the membranous web. By IEM, all HCV proteins were found to be associated with the NS4B-induced membranous web, forming a membrane-associated multiprotein complex. A similar web-like structure in livers of HCV-infected chimpanzees was previously described (Pfeifer et al., Virchows Arch. B., 33:233-243, 1980). In view of this finding and the observation that all HCV proteins accumulate on the membranous web, we propose that the membranous web forms the viral replication complex in HCV-infected cells.

The Hepatitis C Virus RNA-Dependent RNA Polymerase Membrane Insertion Sequence Is a Transmembrane Segment

Abstract: The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) belongs to a class of membrane proteins termed tail-anchored proteins. Here, we show that the HCV RdRp C-terminal membrane insertion sequence traverses the phospholipid bilayer as a transmembrane segment. Moreover, the HCV RdRp was found to be retained in the endoplasmic reticulum (ER) or an ER-derived modified compartment both following transient transfection and in the context of a subgenomic replicon. An absolutely conserved GVG motif was not essential for membrane insertion but possibly provides a docking site for transmembrane protein-protein interactions. These findings have important implications for the functional architecture of the HCV replication complex.

Molecular virology of hepatitis C

Abstract: Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide Here, we will briefly review current concepts of the molecular virology of hepatitis C In vitro and in vivo models of HCV replication will be discussed in this context Finally, novel antiviral strategies will be outlined that result from an improved understanding of the viral life cycle

Viral pathogenesis of hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is one of the most common tumors in the world with an estimated 500 000–1000 000 new cases per year. 1 Although less frequent in the USA and Europe, these tumors have an annual incidence of up to 500 cases per 100000 population in certain regions of Asia and sub-Saharan Africa. The reasons for this high incidence are chronic infections with the hepatitis B virus (HBV) or the hepatitis C virus (HCV) as well as HBV–HCV co-infections. 2–9 The clinical course of HBV and HCV infection depends in part on molecular characteristics of the viruses, 10 in part on the patients’ HLA haplotype, 11–14 and in part on other coexisting risk factors. Well-recognized non-viral exogenous agents associated with the pathogenesis of HCC are alcohol and aflatoxins. In the West, alcoholinduced liver injury is a leading cause of liver cirrhosis and the most important HCC risk factor. 15 In southern China and Africa, dietary ingestion of high levels of aflatoxin B 1 may represent a special environmental hazard, particularly in chronic HBV carriers. 16–19 Other exogenous factors have also been incriminated and include dietary iron overload, 20 long-term use of oral contraceptives 21,22 and high-dose anabolic steroids. The development of hepatic cirrhosis, particularly in association with genetic diseases, such as a -1-antitrypsin deficiency or hemochromatosis, place the individual at a greatly increased risk for the malignant transformation of hepatocytes. In the following, the role of HBV and HCV in the pathogenesis of HCC and strategies aimed at the prevention of HCC will be discussed.

Antiviral treatment of patients with HBV-related cirrhosis.

Abstract: Infection with hepatitis B virus (HBV) is one of the most common viral diseases affecting man. It is an ubiquitous disease of variable geographic prevalence. In Europe and North America only between 0.1 and 1% of the population are infected, whereas in South-East Asia and parts of Africa up to 20% of the population are positive for hepatitis B surface antigen (HBsAg). An estimated 200–300 million people are infected with HBV worldwide. Infection with hepatitis delta virus (HDV) can only take place in conjunction with HBV. The clinical picture in patients infected with HBV and HDV is exceedingly variable and ranges from asymptomatic virus carriers with normal serum transaminases and liver histology to acute or fulminant hepatitis and chronic liver diseases. Chronic HBV infection and HBV-related liver cirrhosis are associated with high morbidity and mortality and are one of the main causes of hepatocellular carcinoma (HCC). 1–8 The clinical course of HBV infection depends in part on molecular characteristics of the virus 9 in part on the patients’ HLA haplotype 10–13 in part on other coexisting risk factors. Well recognized non-viral exogenous agents associated with the pathogenesis of HCC are alcohol and aflatoxin. Treatment of HBV infection is aimed at the prevention of chronic hepatitis B, in patients with chronic hepatitis B at the prevention of liver cirrhosis and HCC development. In the following, the current therapeutic options for patients with chronic hepatitis B and HBVrelated liver cirrhosis as well as therapeutic and preventive perspectives will be discussed.

ER Folgen des Alkohols

Abstract: Ein 54-jahriger Bankangestellter stellt sich im Marz 2000 bei seinem Hausarzt vor. Er leidet seit 4 Wochen an Mudigkeit, Schwache, Gewichtsverlust und rezidivierendem Fieber bis 38°C ohne sonstige fokale Symptome. Auf Befragen berichtet er von regelmasigem Bierkonsum (ca. 1 l Bier/Tag) seit vielen Jahren. Der Hausarzt findet klinische und sonographische Zeichen einer Leberzirrhose und weist ihn aufgrund des unklaren Krankheitsbildes stationar ein.