N-terminal myristoylation-dependent masking of neutralizing epitopes in the preS1 attachment site of hepatitis B virus

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• 作者：Corinna M. Bremer¹ ; Irina Sominskaya² ; Dace Skrastina² ; Paul Pumpens² ; Ahmed Abd El Wahed³ ; Ulrike Beutling⁴ ; Ronald Frank⁴ ; Hans-Joachim Fritz⁵ ; Gerhard Hunsmann³ ; Wolfram H. Gerlich¹ ; Dieter Glebe¹ ; ^{dieter.glebe@viro.med.uni-giessen.de"" rel=""nofollow}
• 关键词：Hepatitis B virus ; preS1 ; Vaccine ; Neutralizing antibodies ; Epitope masking
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：55
• 期：1
• 页码：29-37
• 全文大小：1251 K

文摘

Backgrounds & Aims

The N-terminally myristoylated preS1 domain of the large hepatitis B surface protein (LHBs) mediates specific attachment of hepatitis B virus (HBV) to hepatocytes. Its B-cell epitopes leading to neutralization of infectivity are not yet characterized.

Methods

We inserted C- and N-terminal preS1 peptides into the most immunogenic region of HBV core particles, therewith immunized Balb/c mice and determined binding properties and neutralization potential of resulting antibodies in vitro.

Results

The particles with preS1 inserts were highly immunogenic and the corresponding anti-preS antibodies strongly bound to HBV particles from chronic carriers infected with different HBV genotypes A–F. However, antibodies binding to the C-terminal part of preS1 did not neutralize HBV infectivity for susceptible hepatocyte cultures. In contrast, antibodies elicited by the complete N-terminal attachment site of preS1(2–48) strongly neutralized with an IC50 <3 μg/ml of total immunoglobulin. Interestingly, antibodies against the very N-terminal part of preS1(1–21) could not neutralize infectivity although this sequence contains the most conserved and essential part of the attachment site. These antibodies reacted well with non-myristoylated preS1 peptides but only weakly with myristoylated preS1 peptides, natural HBsAg or HBV.

Conclusions

N-terminal myristic acid obviously favors a topology of LHBs that makes the most essential part of the preS1 attachment site inaccessible for neutralizing antibodies, whereas antibodies to neighbouring sequences neutralized very well. Thus, addition of the preS1(2–48) peptide in a highly immunogenic form to the current hepatitis B vaccine may improve protective immunity and reduce selection of escape mutations.