In Vitro Interaction between Hepatitis C Virus (HCV) Envelope Glycoprotein E2 and Serum Lipoproteins (LPs) Results in Enhanced Cellular Binding of Both HCV E2 and LPs

Journal of Infectious Diseases, Oct 2006

Hepatitis C virus (HCV) particles in serum associate with lipoproteins (LPs), and the low-density lipoprotein receptor (LDLr) has been implicated in virus attachment and entry into cells. To clarify the basis of interactions between virus and LPs, we determined whether HCV interacts with human LPs via its envelope glycoprotein E2. The binding of serum-derived virus-like particles, HCV E2, and HCV E2–LP complexes to CD81 and LDLr was studied. Incubation of HCV E2 protein with human and bovine LPs (very low density, low density, and high density) enhanced the binding of both HCV E2 and LPs to CD4+ lymphoblastoid (MOLT-4) cells, foreskin fibroblasts, and hepatocytes. The binding of HCV E2 to MOLT-4 cells was not enhanced when it was preincubated with lipid-free apoprotein B, which suggests that E2 interacts with the lipid moiety of human lipoproteins. The LP interaction was specific for HCV E2—incubation of HIV gp120 with LPs did not enhance gp120 binding to MOLT-4 cells. The enhanced HCV E2 binding required expression of both human CD81 and LDLr. These data suggest that HCV E2 associates with LDL and that the resulting complex enhances binding of both ligands to cells, which may contribute to the finding that HCV-infected individuals have significantly lower levels of LDL than control subjects

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In Vitro Interaction between Hepatitis C Virus (HCV) Envelope Glycoprotein E2 and Serum Lipoproteins (LPs) Results in Enhanced Cellular Binding of Both HCV E2 and LPs

JID In Vitro Interaction between Hepatitis C Virus (HCV) Envelope Glycoprotein E2 and Serum Lipoproteins (LPs) Results in Enhanced Cellular Binding of Both HCV E2 and LPs Sabina Wu¨ nschmann 2 3 4 Hubert M. Mu¨ ller 0 2 4 Christopher S. Stipp 1 2 4 Martin E. Hemler 1 2 Jack T. Stapleton () 2 3 0 Connex GmbH , Martinsried , Germany 1 Dana-Farber Cancer Institute , Boston, Massachusetts 2 Received 24 March 2006; accepted 30 May 2006; electronically published 8 September 2006. Presented in part: 11th International Symposium on Hepatitis C and Related Viruses , Heidelberg, Germany, 3-7 October 2004 (abstract P-119). Financial support: Veterans Administration (Merit Review grant to J.T.S. ); National Institutes of Health (NIH; grant AI58740 to J.T.S.). Flow cytometry experiments were performed at the University of Iowa Flow Cytometry Facility. HIV anti-gp120 monoclonal antibody was provided by the NIH AIDS Reagent Repository. Potential conflicts of interest: none reported 3 Departments of Internal Medicine and Research, Iowa City Veterans Administration Medical Center, and University of Iowa College of Medicine , Iowa City 4 Present affiliations: INDOOR Biotechnologies, Inc., Charlottesville, Virginia (S.W.); Ascenion GmbH , Munich , Germany ( H.M.M.); Department of Biology, Uni- versity of Iowa , Iowa City (C.S.S.). SW54, GH. 200 Hawkins Dr., Iowa City, IA 52242 Hepatitis C virus (HCV) particles in serum associate with lipoproteins (LPs), and the low-density lipoprotein receptor (LDLr) has been implicated in virus attachment and entry into cells. To clarify the basis of interactions between virus and LPs, we determined whether HCV interacts with human LPs via its envelope glycoprotein E2. The binding of serum-derived virus-like particles, HCV E2, and HCV E2-LP complexes to CD81 and LDLr was studied. Incubation of HCV E2 protein with human and bovine LPs (very low density, low density, and high density) enhanced the binding of both HCV E2 and LPs to CD4+ lymphoblastoid (MOLT-4) cells, foreskin fib oblasts, and hepatocytes. The binding of HCV E2 to MOLT-4 cells was not enhanced when it was preincubated with lipid-free apoprotein B, which suggests that E2 interacts with the lipid moiety of human lipoproteins. The LP interaction was specifi for HCV E2-incubation of HIV gp120 with LPs did not enhance gp120 binding to MOLT-4 cells. The enhanced HCV E2 binding required expression of both human CD81 and LDLr. These data suggest that HCV E2 associates with LDL and that the resulting complex enhances binding of both ligands to cells, which may contribute to the findin that HCV-infected individuals have significantl lower levels of LDL than control subjects. - Hepatitis C virus (HCV) infection is a common cause of morbidity and mortality worldwide (reviewed in [1]). Approximately 80% of infections persist, and 20% of persistent infections progress to chronic liver disease [2]. Because of the long duration between infection and the development of serious liver damage, it has been predicted that there will be a marked increase in liver disease resulting from HCV over the course of the next 25 years [1]. The mechanism(s) by which HCV attaches to and enters cells is not clear. Recombinant HCV envelope glycoprotein (E2) interacts directly with several cell-surface receptors—including CD81 [3], the scavenger receptor B1 [4], DC-SIGN, and L-SIGN [5, 6]— which has led to speculation that these cell-surface molecules may represent components of an HCV cellular receptor complex [3, 7–10]. HCV E2 has consistently been shown to bind CD81, and the presence of CD81 is required, although not sufficient for infectivity of both HCV-pseudotyped retroviruses (HCVpp) [11–13] and cell-culture infectious HCV (HCVcc) [14–16]. CD81 is a member of the tetraspanin family of cellsurface molecules and is expressed on virtually all nucleated cells [17]. HCV exists in different forms in the circulation of infected individuals, and electron-microscopic studies of serum from HCV-infected individuals have demonstrated considerable heterogeneity in particle size, with diameters ranging from 20 to 100 nm [18–20]. This heterogeneity has been explained by the presence of different species of HCV, ranging from nonenveloped and enveloped particles to HCV associated with serum components such as lipoproteins (LPs) and immunoglobulins [18, 20–25]. Material in serum that contains HCV RNA, presumably virus particles, associates with LPs that sediment in sucrose gradients at the buoyant densities of very low density LPs (VLDLs) and low-density LPs (LDLs), 1.06 g/cm3 [7, 21, 23–27]. VLDL is synthesized by the liver and consists of triglycerides, cholesterol, phospholipids, and the apoprotein (apo) B100. The enzymatic digestion of VLDLs in plasma results in intermediate-density LPs (IDLs) and LDLs. The LDL receptor (LDLr) recognizes both apoB100 and apoE and thus binds LDLs, VLDLs, IDLs, and chylomicron remnants [28]. HCV RNA, HCV core protein, and IgG are all (...truncated)


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Sabina Wünschmann, Hubert M. Müller, Christopher S. Stipp, Martin E. Hemler, Jack T. Stapleton. In Vitro Interaction between Hepatitis C Virus (HCV) Envelope Glycoprotein E2 and Serum Lipoproteins (LPs) Results in Enhanced Cellular Binding of Both HCV E2 and LPs, Journal of Infectious Diseases, 2006, pp. 1058-1067, 194/8, DOI: 10.1086/507647