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Impacts of the G145R Mutation on the Structure and Immunogenic Activity of the Hepatitis B Surface Antigen: A
Reza Rezaee1, Mansour Poorebrahim2, Saeideh Najafi3
1Ministry of Health and Medical Education, Deputy of Curative Affairs, Budget Administration, Tehran, IR Iran.
Background:
Vaccine-escaped hepatitis B virus (HBV) mutations occur within the "a" determinant area, which is located in the major hydrophilic region (MHR) of the hepatitis B surface antigen (HBsAg) protein. It is now well established that the common G145R mutation is highly capable of escaping from HBsAg immune recognition. However, the impacts of this mutation on the structure and immunogenic activity of HBsAg have been poorly investigated.
Objectives:
The present study analyzed the effects of the G145R mutation on the structure and immunogenic activity of the HBsAg.
Materials And Methods:
Three-dimensional (3D) structure of HBsAg for both the wild-type and G145R mutant were predicted and refined using several web tools. After quantitative evaluations, the effects of the G145R mutation on the secondary and 3D structures of the HBsAg were investigated. In parallel, the immunogenic activity of the wild-type and mutant HBsAg was also analyzed using a ClusPro docking server as well as the IEDB web tool. Further analyses were performed via molecular dynamics (MD) simulations using the GROMACS v5.0.2 simulation package.
Results:
The G145R mutation causes a considerable reduction in the immunogenic activity of the HBsAg through a conformational change in the HBsAg antigenic loops. This mutation inserts a new β-strand in the "a" determinant region of the HBsAg, leading to a reduced binding affinity to its monoclonal antibody, MAb12. The G145R mutation also increased the compactness and stability of the HBsAg by enhancing the rigidity of the "a" determinant.
Conclusions:
These data will be beneficial for designing more advanced antibodies for the recognition of the HBsAg in diagnostics. In addition, the results of this study may assist in the design or development of more effective hepatitis B vaccines.
Insights
The G145R mutation in hepatitis B surface antigen (HBsAg) alters its structure, reducing immune recognition and antibody binding. This finding aids in developing improved diagnostics and vaccines for hepatitis B virus (HBV).
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Hepatitis B virus (HBV) vaccine-escape mutations arise in the HBsAg "a" determinant.
- The G145R mutation is known to evade immune recognition but its structural and immunogenic impacts are understudied.
Purpose of the Study:
- To investigate the structural and immunogenic consequences of the G145R mutation in HBsAg.
- To analyze how G145R affects HBsAg's interaction with antibodies.
Main Methods:
- 3D structure prediction and refinement of wild-type and G145R mutant HBsAg.
- Analysis of secondary and 3D structural changes using web tools and molecular dynamics simulations.
- Immunogenic activity assessment via ClusPro docking and IEDB web tool.
Main Results:
- G145R mutation induces conformational changes in HBsAg antigenic loops, reducing immunogenicity.
- A new β-strand forms in the "a" determinant, decreasing binding affinity to MAb12.
- The mutation enhances HBsAg compactness and stability by increasing "a" determinant rigidity.
Conclusions:
- Findings provide insights for designing novel diagnostic antibodies targeting HBsAg.
- Results may contribute to the development of more effective hepatitis B vaccines.
