Formation of native hepatitis C virus glycoprotein complexes

Deleersnyder, Virginie; Pillez, André; Wychowski, Czeslaw; Blight, Keril J.; Xu, Jian; Hahn, Young Y.S.; Rice, Charles C.M.; Dubuisson, Jean

doi:10.1128/jvi.71.1.697-704.1997

Cited by 283 publications

(136 citation statements)

References 36 publications

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“…Jopling et al, 2005;Kaul et al, 2009). Virion assembly is initiated on core-coated lipid droplets followed by budding into the ER, where the two envelope glycoproteins, E1 and E2, form non-covalently-bonded heterodimers and disulphide-bonded aggregates (Dubuisson et al, 1994;Deleersnyder et al, 1997;Lindenbach and Rice, 2013). Virus particles are released via trafficking through the secretory pathway, where the envelope proteins undergo further glycan modifications and structural rearrangement into higher ordered oligomeric aggregates (Vieyres et al, 2010(Vieyres et al, , 2014.…”

Section: Hepatitis C Virus Life Cyclementioning

confidence: 99%

“…After importing into the ER by signal peptides at their respective N-termini, they are cleaved into E1 and E2 by cellular signal peptidase (Hijikata et al, 1991a;Lin et al, 1994). Inside the ER, E1 and E2 form two types of complexes: non-covalently-bonded E1-E2 heterodimer and disulphide-bonded aggregates, neither is the mature form (Dubuisson et al, 1994;Dubuisson and Rice, 1996;Deleersnyder et al, 1997). It is not clear which of these forms of E1E2 is acquired by the virion when the virus buds into the ER as E1E2 undergo further conformational changes into aggregated oligomers when the virus particles transit through the secretory pathway (Vieyres et al, 2010(Vieyres et al, , 2014.…”

Section: Immature Virion As Upr Inducermentioning

confidence: 99%

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Unfolded protein response in hepatitis C virus infection

Chan

2014

Front. Microbiol.

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Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus of clinical importance. The virus establishes a chronic infection and can progress from chronic hepatitis, steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The mechanisms of viral persistence and pathogenesis are poorly understood. Recently the unfolded protein response (UPR), a cellular homeostatic response to endoplasmic reticulum (ER) stress, has emerged to be a major contributing factor in many human diseases. It is also evident that viruses interact with the host UPR in many different ways and the outcome could be pro-viral, anti-viral or pathogenic, depending on the particular type of infection. Here we present evidence for the elicitation of chronic ER stress in HCV infection. We analyze the UPR signaling pathways involved in HCV infection, the various levels of UPR regulation by different viral proteins and finally, we propose several mechanisms by which the virus provokes the UPR.

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Section: Hepatitis C Virus Life Cyclementioning

confidence: 99%

Section: Immature Virion As Upr Inducermentioning

confidence: 99%

Unfolded protein response in hepatitis C virus infection

Chan

2014

Front. Microbiol.

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“…Recognition by mAb H33 is of particular relevance, because this antibody is specific for a conformation and time-dependent epitope on nondisulfide-bridged E2 in complex with E1, believed to represent "native" prebudding forms of the HCV envelope. 61 These data led to the conclusion that both mimotopic and HVR1-deleted recombinants are folded. This folding must be very similar to that of native E2 on the virus, because mimotope/E2 fusion proteins efficiently bound CD81, shown to interact with HCV via E2 in a conformationdependent way.…”

Section: Discussionmentioning

confidence: 99%

Mimotopes of the hepatitis C virus hypervariable region 1, but not the natural sequences, induce cross-reactive antibody response by genetic immunization

Zucchelli¹,

Roccasecca²,

Meola³

et al. 2001

Hepatology

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The hypervariable region 1 (HVR1) of the putative envelope protein E2 of hepatitis C virus (HCV) contains a principal neutralization epitope, and anti-HVR1 antibodies have been shown to possess protective activity in ex vivo neutralization experiments. However, the high rate of variability of this antigenic fragment may play a major role in the mechanism of escape from host immune response and might represent a major obstacle to developing an HCV vaccine. Thus, even if direct experimental evidence of the neutralizing potential of anti-HVR1 antibodies by active immunization is still missing, the generation of a vaccine candidate with a cross-reactive potential would be highly desirable. Hepatitis C virus (HCV) is the major etiologic agent of blood transfusion-associated and sporadic non-A non-B hepatitis worldwide, with an estimated prevalence of 0.4% to 2% in the blood donor population. 1 Despite a wide array of humoral and cell-mediated host immune responses, HCV infection leads to chronic disease in about 70% of cases, among which a significant proportion eventually develops cirrhosis and hepatocellular carcinoma. 2 Interferon treatment (also in combination with ribavirin) is the only antiviral therapy available at the moment, but it is effective only in 20% to 40% of patients, 3-5 thus making the development of an HCV vaccine a high priority target.Vaccination of chimpanzees (the only other species susceptible to HCV infection) using recombinant forms of the putative envelope proteins E1 and E2 has been shown to induce protective immunity against low-dose challenge with the homologous virus, whose efficacy seems to correlate with the titer of anti-E2 antibodies. [6][7][8] More recently, HCV was shown to bind to its putative receptor component CD81 via E2. 9 These data point toward the E2 protein as a likely candidate for vaccine development. However, a major concern still remains as to whether the anti-E2 response elicited by one recombinant protein would be effective against heterologous viral inocula. 10 In fact, HCV displays a high rate of mutation during replication and exists in the bloodstream of infected patients as a quasispecies, [11][12][13][14][15] which fluctuates during the course of the disease mainly as a result of immune pressure. [15][16][17][18][19][20][21][22][23] The major target of this immune response is the 27 amino acid-long N-terminal segment of the E2 glycoprotein. This protein fragment is the most variable region of the whole HCV polyprotein 11 and contains a principal neutralization determinant, 24 but anti-hypervariable region 1 (HVR1) antibodies specific for one variant display only a limited ability to block different viral variants. 24 In this scenario, the most difficult task in developing an HCV vaccine would be to find a solution to the issue of viral variability.We have recently described a novel approach to this problem by selecting highly cross-reacting "synthetic variants" of the HCV HVR1 from a vast repertoire of HVR1 surrogates as fusion to the major coat protein of ba...

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“…# GB10416) was from Genesis Biotech (Xindian, Taipei County, Taiwan). H53 MAb was an E2 conformation-specific MAb [6,65]. Hybridoma 183 (clone H12-5C) secretes an MAb that specifically recognizes HIV-1 capsid protein p24 as previously described [66].…”

Section: Cells and Antibodiesmentioning

confidence: 99%

“…E1 and E2 form a non-covalent heterodimer [1] and are heavily N-linked glycosylated type I integral transmembrane proteins, with an N-terminal ectodomain and a C-terminal hydrophobic anchor domains (reviewed in [2,3]). E1 and E2 associate to form two types of complexes: (i) heterodimers stabilized by non-covalent bonds, which probably represent the prebudding and functional form of the viral envelope; and (ii) highmolecular-mass disulfide-bonded aggregates, which may represent misfolded proteins [4][5][6][7]. Both types of complexes are retained in endoplasmic reticula (ER), the proposed site for HCV assembly and budding.…”

Section: Introductionmentioning

confidence: 99%

Mutagenesis of the fusion peptide-like domain of hepatitis C virus E1 glycoprotein: involvement in cell fusion and virus entry

Huang

et al. 2009

J Biomed Sci

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BackgroundEnvelope (E) glycoprotein E2 of the hepatitis C virus (HCV) mediates binding of the virus to target cell receptors. Nevertheless, the precise role of E1 in viral entry remains elusive.MethodsTo understand the involvement of the fusion peptide-like domain positioned at residues 264 to 290 within envelope glycoprotein E1 in HCV infection, mutants with Ala and Asn substitutions for residues conserved between HCV and E proteins of flaviviruses or the fusion proteins of paramyxoviruses were constructed by site-directed mutagenesis and their effects on membrane fusion and viral infectivity were examined.ResultsNone of these mutations affected the synthesis or cell surface expression of envelope proteins, nor did they alter the formation of a non-covalent E1-E2 heterodimer or E2 binding to the large extracellular loop of CD81. The Cys residues located at positions 272 and 281 were unlikely involved in intra- or intermolecular disulfide bond formation. With the exception of the G267A mutant, which showed increased cell fusion, other mutants displayed reduced or marginally inhibited cell fusion capacities compared to the wild-type (WT) E1E2. The G267A mutant was also an exception in human immunodeficiency virus type 1 (HIV-1)/HCV E1E2 pseudotyping analyses, in that it showed higher one-cycle infectivity; all other mutants exhibited greatly or partially reduced viral entry versus the WT pseudotype. All but the G278A and D279N mutants showed a WT-like profile of E1E2 incorporation into HIV-1 particles. Since C272A, C281A, G282A, and G288A pseudotypes bound to Huh7 cells as effectively as did the WT pseudotype, the reduced infectivity of these pseudotypes was due to their ability to inhibit cell fusion.ConclusionOur results indicate that specific residues, but not the structure, of this fusion peptide-like domain are required for mediating cell fusion and viral entry.

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Formation of native hepatitis C virus glycoprotein complexes

Cited by 283 publications

References 36 publications

Unfolded protein response in hepatitis C virus infection

Unfolded protein response in hepatitis C virus infection

Mimotopes of the hepatitis C virus hypervariable region 1, but not the natural sequences, induce cross-reactive antibody response by genetic immunization

Mutagenesis of the fusion peptide-like domain of hepatitis C virus E1 glycoprotein: involvement in cell fusion and virus entry

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