Role for Calnexin and N-Linked Glycosylation in the Assembly and Secretion of Hepatitis B Virus Middle Envelope Protein Particles

Werr, Margaret; Prange, Reinhild

doi:10.1128/jvi.72.1.778-782.1998

Cited by 63 publications

(44 citation statements)

References 24 publications

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“…In addition to the Asn-201 (Asn-146 on the S protein), the preS2 domain contains an N-glycosylation site at Asn-4 together with an optional O-glycosylation site at Thr-37 depending on the genotype (Heermann et al, 1984;Tolle et al, 1998). Interestingly, a strict correlation between glycan-dependent chaperone binding and secretion of M indicates that ER proteins such as calnexin promote folding and trafficking of M allowing particle secretion (Werr and Prange, 1998). However, the exact role of M in the viral cycle remains unclear.…”

Section: Hbv Envelopementioning

confidence: 99%

Morphogenesis of hepatitis B virus and its subviral envelope particles

Patient¹,

Hourioux

Roingeard³

2009

Cellular Microbiology

134

136

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SummaryAfter cell hijacking and intracellular amplification, non-lytic enveloped viruses are usually released from the infected cell by budding across internal membranes or through the plasma membrane. The enveloped human hepatitis B virus (HBV) is an example of virus using an intracellular compartment to form new virions. Four decades after its discovery, HBV is still the primary cause of death by cancer due to a viral infection worldwide. Despite numerous studies on HBV genome replication little is known about its morphogenesis process. In addition to viral neogenesis, the HBV envelope proteins have the capability without any other viral component to form empty subviral envelope particles (SVPs), which are secreted into the blood of infected patients. A better knowledge of this process may be critical for future antiviral strategies. Previous studies have speculated that the morphogenesis of HBV and its SVPs occur through the same mechanisms. However, recent data clearly suggest that two different processes, including constitutive Golgi pathway or cellular machinery that generates internal vesicles of multivesicular bodies (MVB), independently form these two viral entities.

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Section: Hbv Envelopementioning

confidence: 99%

Morphogenesis of hepatitis B virus and its subviral envelope particles

Patient¹,

Hourioux

Roingeard³

2009

Cellular Microbiology

134

136

View full text Add to dashboard Cite

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“…Resistance to proteasomal degradation might contribute to HBV being refractory to presentation by MHC class I and even to establishment of chronicity 6. However, compared to most cellular N ‐glycoproteins, and even the SHBs, the MHBs protein is unusually dependent on calnexin‐mediated protein folding 7, 8. Calnexin is a cellular lectin chaperone that recognizes N ‐glycans on nascent proteins that have been trimmed to a monoglucose residue 9, 10.…”

mentioning

confidence: 99%

Glucosidase Inhibition Enhances Presentation of De– N -Glycosylated Hepatitis B Virus Epitopes by Major Histocompatibility Complex Class I In Vitro and in Woodchucks

et al. 2010

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In this report, the possibility of pharmacologically altering the hepatitis B virus (HBV) epitopes presented by major histocompatibility complex class I on infected cells is demonstrated. The HBV middle envelope glycoprotein (MHBs) maturation appears to require calnexin-mediated folding. This interaction is dependent on glucosidases in the endoplasmic reticulum. Prevention of HBV envelope protein maturation in cultured cells through use of glucosidase inhibitors, such as 6-O-butanoyl castanospermine and N-nonyl deoxynorjirimycin, resulted in MHBs degradation by proteasomes. The de-N-glycosylation associated with polypeptide degradation was predicted to result in conversion of asparagine residues into aspartic acid residues. This prediction was confirmed by showing that peptides corresponding to the N-glycosylation sequons of MHBs, but with aspartic acid replacing asparagine, (1) can prime human cytotoxic T lymphocytes that recognize HBVproducing cells and (2) that the presentation of these envelope motifs by major histocompatibility complex class I is enhanced by incubation with glucosidase inhibitors. Moreover, although peripheral blood mononuclear cells isolated from woodchucks chronically infected with woodchuck hepatitis virus and vaccinated with woodchuck hepatitis virus surface antigen could be induced to recognize the natural MHBs asparagine-containing peptides, only cells isolated from animals treated with glucosidase inhibitor recognized the aspartic acid-containing peptides. Conclusion: These data suggest that pharmacological intervention with glucosidase inhibitors can alter the MHBs epitopes presented. This editing of the amino acid sequence of the polypeptide results in a new epitope, or ''editope'', with possible medical significance. (HEPATOLOGY 2010;52:1242-1250 C hronic infection with hepatitis B virus (HBV) is characterized by a lack of robust T cell responsiveness to viral antigens. 1,2 Indeed, an inadequate CD8þ T cell response is thought to be key to the establishment of chronicity. Typically, virusspecific CD8þ cytotoxic T lymphocytes (CTLs) are elicited by infected cells presenting virus-derived peptides by major histocompatibility complex (MHC) class I. However, poor CTL responses in chronic HBV infection are likely a consequence of multiple factors, 1,2 including viral interference with efficient processing and presentation of HBV epitopes.3 Thus, methods that can cause enhanced recognition or presentation of viral epitopes by MHC class I might be useful as therapeutic interventions and as research tools.Viral glycoproteins represent important targets for any antiviral immune response. HBV is an enveloped

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“…For example, by disrupting the calnexin-mediated folding of one or more of the HBV glycoproteins, glucosidase inhibitors prevent the formation and secretion of HBV. [7][8][9][10][11]16,17 Previously we reported the use of the imino sugar N-nonyl-DNJ in the woodchuck model of chronic HBV infection. 11 This compound exhibited antiviral activity with no observed toxicity.…”

mentioning

confidence: 99%

Inhibition of Hepatitis B Virus Dna Replication by Imino Sugars Without the Inhibition of the Dna Polymerase: Therapeutic Implications

Mehta¹,

Carrouée

Conyers³

et al. 2001

Hepatology

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Previously we have shown that the imino sugar inhibitor of N-linked glycan processing, N-nonyl-deoxynojirimycin (N-nonyl-DNJ), had antiviral activity in the woodchuck model of chronic hepatitis B virus (HBV) infection. In studying the mechanism of action of this compound, it was discovered that imino sugars could inhibit HBV secretion without inhibiting N-linked glycoprocessing. Although Nnonyl-DNJ is an inhibitor of the endoplasmic reticulum (ER) glucosidase, here it is shown that N-nonyl-DNJ retained antiviral activity at concentrations that had no significant impact on ER glucosidase function. Taken together, these results suggested that N-nonyl-DNJ possessed an antiviral activity attributable to a function other than an impact on glycoprocessing. Hepatitis B virus (HBV) is the prototypic member of the hepadnaviradae family of viruses, which includes duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. 1 Worldwide, more than 350 million people are chronically infected with HBV and between 15% and 40% of these individuals will die, if left untreated, from serious liver diseases. 2 The major complication is the development of (primary) hepatocellular carcinoma, which causes an estimated 500,000 deaths annually. 3 Currently there is no definitive cure for chronic HBV infection; however, several FDA (United States Food and Drug Administration) approved clinical approaches have shown promise in some individuals. The first, interferon ␣, is an immunomodulator and has shown to be effective in achieving certain serologic milestones in between 7% and 40% of treated patients. 4 However, the need for parenteral administration, the poor long-term response, and the high frequency of adverse side effects makes interferon not ideal. 4 Also, the actual basis of the activity of interferon ␣ against HBV is unclear. The other FDA-approved HBV medicine is a nucleoside analogue, "3TC-lamivudine," now sold as "lamivudine/Epivir HBV." It is effective against human immunodeficiency virus, as well as HBV, and its mechanism of action is well understood: it is a competitive inhibitor of the viral reverse transcriptase. 5 Unlike interferon, it is orally available and effective in reducing viremia in almost all patients. 6 However, constitutive therapy is necessary and, unfortunately, escape mutants that have gained resistance to 3TC-lamivudine occur in 10% to 20% of those treated per year. Sadly, after 3 years of use, almost 70% of those treated were, again, viremic with HBV. 6 Although the pathogenicity of 3TC-lamivudineresistant escape mutants is uncertain, there clearly remains a need for alternatives and complements to interferon and the nucleoside analogues such as 3TC-lamivudine.N-butyl-deoxynojirimycin (N-butyl-DNJ) and N-nonyldeoxynojirimycin (N-nonyl-DNJ) are glucosidase inhibitors that have been shown to be antiviral against HBV in tissue culture and in the woodchuck model of chronic HBV infection. 7-11 The ␣-glucosidases (I and II) mediate the first steps in the glycan-processing pathway and a...

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Role for Calnexin and N-Linked Glycosylation in the Assembly and Secretion of Hepatitis B Virus Middle Envelope Protein Particles

Cited by 63 publications

References 24 publications

Morphogenesis of hepatitis B virus and its subviral envelope particles

Morphogenesis of hepatitis B virus and its subviral envelope particles

Glucosidase Inhibition Enhances Presentation of De– N -Glycosylated Hepatitis B Virus Epitopes by Major Histocompatibility Complex Class I In Vitro and in Woodchucks

Inhibition of Hepatitis B Virus Dna Replication by Imino Sugars Without the Inhibition of the Dna Polymerase: Therapeutic Implications

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