Impaired Virion Secretion by Hepatitis B Virus Immune Escape Mutants and Its Rescue by Wild-Type Envelope Proteins or a Second-Site Mutation

Kwei, Karen; Tang, Xiaoli; Lok, Anna S.; Sureau, Camille; Garcia, Tamako; Li, Jisu; Wands, Jack R.; Tong, Shuping

doi:10.1128/jvi.02701-12

Cited by 54 publications

(64 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2), but it led to a decrease in HBV virion production, as previously reported (35). This defect was not due to the reduced synthesis or stability of the nonglycosylated L-HBsAg mutant compared to that of the wt.…”

Section: Discussionsupporting

confidence: 60%

“…Only in a few cases of chronic infection is this pattern modified to include an additional site (35), a strategy used more extensively by other enveloped viruses, such as HIV or hepatitis C virus, to escape neutralizing antibodies (13). In this study, the functions underlying the peculiar glycosylation pattern of HBV envelope proteins were explored, in particular with respect to position 146 in the AGL at which N-glycosylation occurs and the systematic coexistence of glycosylated and nonglycosylated N146.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Modification of the Hepatitis B Virus Envelope Protein Glycosylation Pattern Interferes with Secretion of Viral Particles, Infectivity, and Susceptibility to Neutralizing Antibodies

Julithe

Abou-Jaoudé

Sureau

2014

J Virol

Self Cite

View full text Add to dashboard Cite

The envelope proteins of hepatitis B virus (HBV) bear an N-linked glycosylation site at N146 within the immunodominant a-determinant in the antigenic loop (AGL) region. This glycosylation site is never fully functional, leading to a nearly 1/1 ratio of glycosylated/nonglycosylated isoforms in the viral envelope. Here we investigated the requirement for a precise positioning of Nlinked glycan at amino acid 146 and the functions associated with the glycosylated and nonglycosylated isoforms. We observed that the removal of the N146 glycosylation site by mutagenesis was permissive to envelope protein synthesis and stability and to secretion of subviral particles (SVPs) and hepatitis delta virus (HDV) virions, but it was detrimental to HBV virion production. Several positions in the AGL could substitute for position 146 as the glycosylation acceptor site. At position 146, neither a glycan chain nor asparagine was absolutely required for infectivity, but there was a preference for a polar residue. Envelope proteins bearing 5 AGL glycosylation sites became hyperglycosylated, leading to an increased capacity for SVP secretion at the expense of HBV and HDV virion secretion. Infectivity-compatible N-glycosylation sites could be inserted at 3 positions (positions 115, 129, and 136), but when all three positions were glycosylated, the hyperglycosylated mutant was substantially attenuated at viral entry, while it acquired resistance to neutralizing antibodies. Taken together, these findings suggest that the nonglycosylated N146 is essential for infectivity, while the glycosylated form, in addition to its importance for HBV virion secretion, is instrumental in shielding the a-determinant from neutralizing antibodies. IMPORTANCEAt the surface of HBV particles, the immunodominant a-determinant is the main target of neutralizing antibodies and an essential determinant of infectivity. It contains an N-glycosylation site at position 146, which is functional on only half of the envelope proteins. Our data suggest that the coexistence of nonglycosylated and glycosylated N146 at the surface of HBV reflects the dual function of this determinant in infectivity and immune escape. Hence, a modification of the HBV glycosylation pattern affects not only virion assembly and infectivity but also immune escape.T he hepatitis B virus (HBV) is an enveloped DNA virus and the prototype of the Hepadnaviridae family. HBV is characterized by a strict tropism for human hepatocytes and the ability to cause acute and chronic infections. It is estimated that worldwide, approximately 240 million individuals are HBV chronic carriers and are at risk of developing liver cirrhosis and hepatocellular carcinoma (1). HBV hepatotropism is determined, for the most part, by the HBV envelope proteins at viral entry. A single open reading frame in the HBV genome encodes three envelope proteins that differ from each other by the size of their N-terminal ectodomain. They bear the HBV surface antigen (HBsAg) in their common S domain and are referred to as the l...

show abstract

Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Modification of the Hepatitis B Virus Envelope Protein Glycosylation Pattern Interferes with Secretion of Viral Particles, Infectivity, and Susceptibility to Neutralizing Antibodies

Julithe

Abou-Jaoudé

Sureau

2014

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, we detected 10 mutation sites at the 'a' determinant. Previous studies suggested that genetic changes in the antigenic epitopes might alter the conformation of immunogenic determinants, which reduce binding affinity to relevant immune molecules and induce the mutant escape from immune surveillance (25,26). Therefore, the mutations in these epitopes may have contributed to the persistence of HBV infection.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 1368 full-length RT sequences were obtained from the cross-sectional study subjects (IT: 479, IA: 461, and IC: 428, respectively). The number of sequences per sample in IT, IA and IC phases were 23 (22)(23)(24)(25)(26), 23 (21)(22)(23)(24)(25)(26)(27) and 20 (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), respectively (P = 0.10). Another 1147 sequences (49% from the cross-sectional study) were obtained for the longitudinal analysis.…”

Section: Clinical Characteristicsmentioning

confidence: 98%

A strong conservative tendency in HBV transcriptase (RT): a majority of natural RT mutations derived from the S gene

Song

et al. 2016

Liver International

View full text Add to dashboard Cite

show abstract

“…Cloning of the RT domain alone will only give essential information about changes within the S domain, e.g. stop mutations that can lead to secretion-deficient variants [9], or other mutations within the antigenic determinant, responsible for HBV immune escape [10,11,12,13] and their transmission [14]. …”

Section: Amplification and Cloning Of Hbv Genome Variantsmentioning

confidence: 99%

Selected Phenotypic Assays Used to Evaluate Antiviral Resistance and Viral Fitness of Hepatitis B Virus and Its Variants

Glebe¹,

Geipel²

2014

Intervirology

View full text Add to dashboard Cite

Currently available antiviral therapies specifically target viral replication by blocking reverse transcription with orally given nucleos(t)ide analogues and are able to specifically suppress viral replication. The unique replication strategy of hepatitis B virus (HBV), however, allows long-term persistence of the viral genome within infected hepatocytes in spite of successful therapy. Thus, antiviral therapy needs to be continued for years. Therapy can result either in the emergence and selection of antiviral-resistant variants or the relapse of viral replication after the termination of antiviral therapy. Resistance is a major problem for 4 of the 5 approved HBV nucleos(t)ide analogues, but it is not the only reason for therapy failure. An accurate phenotypic in vitro assay for resistance allows the identification of a viral variant selected in vivo during antiviral therapy and helps to find therapeutic alternatives. Furthermore, these assays can be used to measure viral fitness and pathogenicity in vitro. With the help of these assays, the prediction of emerging viral variants with drug resistance or increased pathogenic potential can be realized. Phenotypic resistance tests for HBV are not trivial because the virus cannot be readily grown in cell culture. This review focuses on currently available phenotypic assays to evaluate antiviral resistance of HBV and fitness of viral variants in general.

show abstract

Impaired Virion Secretion by Hepatitis B Virus Immune Escape Mutants and Its Rescue by Wild-Type Envelope Proteins or a Second-Site Mutation

Cited by 54 publications

References 42 publications

Modification of the Hepatitis B Virus Envelope Protein Glycosylation Pattern Interferes with Secretion of Viral Particles, Infectivity, and Susceptibility to Neutralizing Antibodies

Modification of the Hepatitis B Virus Envelope Protein Glycosylation Pattern Interferes with Secretion of Viral Particles, Infectivity, and Susceptibility to Neutralizing Antibodies

A strong conservative tendency in HBV transcriptase (RT): a majority of natural RT mutations derived from the S gene

Selected Phenotypic Assays Used to Evaluate Antiviral Resistance and Viral Fitness of Hepatitis B Virus and Its Variants

Contact Info

Product

Resources

About