scholarly journals Diverse CD81 Proteins Support Hepatitis C Virus Infection

2006 ◽  
Vol 80 (22) ◽  
pp. 11331-11342 ◽  
Author(s):  
Mike Flint ◽  
Thomas von Hahn ◽  
Jie Zhang ◽  
Michelle Farquhar ◽  
Christopher T. Jones ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Viral Entry ◽  
Hepatitis C Virus Infection ◽  
Extracellular Loop ◽  
Virus Attachment ◽  
Susceptibility To Infection ◽  
Cell Incubation ◽  
Large Extracellular Loop

ABSTRACT Hepatitis C virus (HCV) entry is dependent on CD81. To investigate whether the CD81 sequence is a determinant of HCV host range, we expressed a panel of diverse CD81 proteins and tested their ability to interact with HCV. CD81 large extracellular loop (LEL) sequences were expressed as recombinant proteins; the human and, to a low level, the African green monkey sequences bound soluble HCV E2 (sE2) and inhibited infection by retrovirus pseudotype particles bearing HCV glycoproteins (HCVpp). In contrast, mouse or rat CD81 proteins failed to bind sE2 or to inhibit HCVpp infection. However, CD81 proteins from all species, when expressed in HepG2 cells, conferred susceptibility to infection by HCVpp and cell culture-grown HCV to various levels, with the rat sequence being the least efficient. Recombinant human CD81 LEL inhibited HCVpp infectivity only if present during the virus-cell incubation, consistent with a role for CD81 after virus attachment. Amino acid changes that abrogate sE2 binding (I182F, N184Y, and F186S, alone or in combination) were introduced into human CD81. All three amino acid changes in human CD81 resulted in a molecule that still supported HCVpp infection, albeit with reduced efficiency. In summary, there is a remarkable plasticity in the range of CD81 sequences that can support HCV entry, suggesting that CD81 polymorphism may contribute to, but alone does not define, the HCV susceptibility of a species. In addition, the capacity to support viral entry is only partially reflected by assays measuring sE2 interaction with recombinant or full-length CD81 proteins.

scholarly journals Amino Acid Substitutions Associated with Treatment Failure for Hepatitis C Virus Infection

2020 ◽  
Vol 58 (12) ◽  
Author(s):  
María Eugenia Soria ◽  
Carlos García-Crespo ◽  
Brenda Martínez-González ◽  
Lucía Vázquez-Sirvent ◽  
Rebeca Lobo-Vega ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Treatment Failure ◽  
Antiviral Agents ◽  
Three Dimensional ◽  
Sustained Viral Response ◽  
Amino Acid Substitutions ◽  
Hepatitis C Virus Infection ◽  
Bona Fide

ABSTRACT Despite the high virological response rates achieved with current directly acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. The identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultradeep sequencing (UDS) methods, for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV, which are not bona fide resistance-associated substitutions (RAS), from 220 patients who failed therapy. They were present frequently in basal and posttreatment virus of patients who failed different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. They also have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value for treatment response, are discussed.

Neutralizing Host Responses in Hepatitis C Virus Infection Target Viral Entry at Postbinding Steps and Membrane Fusion

2008 ◽  
Vol 135 (5) ◽  
pp. 1719-1728.e1 ◽  
Author(s):  
Anita Haberstroh ◽  
Eva K. Schnober ◽  
Mirjam B. Zeisel ◽  
Patric Carolla ◽  
Heidi Barth ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Membrane Fusion ◽  
Viral Entry ◽  
Host Responses ◽  
Hepatitis C Virus Infection

607 NEUTRALIZING HOST RESPONSES IN HEPATITIS C VIRUS INFECTION TARGET VIRAL ENTRY AT POST-BINDING STEPS AND MEMBRANE FUSION

2008 ◽  
Vol 48 ◽  
pp. S226
Author(s):  
A. Haberstroh ◽  
E.K. Schnober ◽  
P. Carolla ◽  
M.B. Zeisel ◽  
H. Barth ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Membrane Fusion ◽  
Viral Entry ◽  
Host Responses ◽  
Hepatitis C Virus Infection

scholarly journals Identification of the Hepatitis C Virus E2 Glycoprotein Binding Site on the Large Extracellular Loop of CD81

2002 ◽  
Vol 76 (21) ◽  
pp. 11143-11147 ◽  
Author(s):  
Heidi E. Drummer ◽  
Kirilee A. Wilson ◽  
Pantelis Poumbourios
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Site ◽  
Nk Cell ◽  
Cell Activity ◽  
Random Mutagenesis ◽  
Extracellular Loop ◽  
Human T Cell ◽  
Large Extracellular Loop

ABSTRACT The binding of hepatitis C virus glycoprotein E2 to the large extracellular loop (LEL) of CD81 has been shown to modulate human T-cell and NK cell activity in vitro. Using random mutagenesis of a chimera of maltose-binding protein and LEL residues 113 to 201, we have determined that the E2-binding site on CD81 comprises residues Ile182, Phe186, Asn184, and Leu162. These findings reveal an E2-binding surface of approximately 806 Å2 and potential target sites for the development of small-molecule inhibitors of E2 binding.

scholarly journals Conservation of the Conformation and Positive Charges of Hepatitis C Virus E2 Envelope Glycoprotein Hypervariable Region 1 Points to a Role in Cell Attachment

2001 ◽  
Vol 75 (12) ◽  
pp. 5703-5710 ◽  
Author(s):  
François Penin ◽  
Christophe Combet ◽  
Georgios Germanidis ◽  
Pierre-Olivier Frainais ◽  
Gilbert Deléage ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Viral Entry ◽  
Envelope Glycoprotein ◽  
Cell Attachment ◽  
Hypervariable Region ◽  
Amino Acid Sequences ◽  
Specific Sequence ◽  
Amino Acid Region

ABSTRACT Chronic hepatitis C virus (HCV) infection is a major cause of liver disease. The HCV polyprotein contains a hypervariable region (HVR1) located at the N terminus of the second envelope glycoprotein E2. The strong variability of this 27-amino-acid region is due to its apparent tolerance of amino acid substitutions together with strong selection pressures exerted by anti-HCV immune responses. No specific function has so far been attributed to HVR1. However, its presence at the surface of the viral particle suggests that it might be involved in viral entry. This would imply that HVR1 is not randomly variable. We sequenced 460 HVR1 clones isolated at various times from six HCV-infected patients receiving alpha interferon therapy (which exerts strong pressure towards quasispecies genetic evolution) and analyzed their amino acid sequences together with those of 1,382 nonredundant HVR1 sequences collected from the EMBL database. We found that (i) despite strong amino acid sequence variability related to strong pressures towards change, the chemicophysical properties and conformation of HVR1 were highly conserved, and (ii) HVR1 is a globally basic stretch, with the basic residues located at specific sequence positions. This conservation of positively charged residues indicates that HVR1 is involved in interactions with negatively charged molecules such as lipids, proteins, or glycosaminoglycans (GAGs). As with many other viruses, possible interaction with GAGs probably plays a role in host cell recognition and attachment.

scholarly journals Amphipathic DNA Polymers Inhibit Hepatitis C Virus Infection by Blocking Viral Entry

2009 ◽  
Vol 137 (2) ◽  
pp. 673-681 ◽  
Author(s):  
Takuya Matsumura ◽  
Zongyi Hu ◽  
Takanobu Kato ◽  
Marlene Dreux ◽  
Yong–Yuan Zhang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Viral Entry ◽  
Hepatitis C Virus Infection
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