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Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
- Publisher :
- Proceedings of the National Academy of Sciences, 2021.
-
Abstract
- Hepatitis C virus (HCV) is a major worldwide health burden, and a preventive vaccine is needed for global control or eradication of this virus. A substantial hurdle to an effective HCV vaccine is the high variability of the virus, leading to immune escape. The E1E2 glycoprotein complex contains conserved epitopes and elicits neutralizing antibody responses, making it a primary target for HCV vaccine development. However, the E1E2 transmembrane domains that are critical for native assembly make it challenging to produce this complex in a homogenous soluble form that is reflective of its state on the viral envelope. To enable rational design of an E1E2 vaccine, as well as structural characterization efforts, we have designed a soluble, secreted form of E1E2 (sE1E2). As with soluble glycoprotein designs for other viruses, it incorporates a scaffold to enforce assembly in the absence of the transmembrane domains, along with a furin cleavage site to permit native-like heterodimerization. This sE1E2 was found to assemble into a form closer to its expected size than full-length E1E2. Preservation of native structural elements was confirmed by high-affinity binding to a panel of conformationally specific monoclonal antibodies, including two neutralizing antibodies specific to native E1E2 and to its primary receptor, CD81. Finally, sE1E2 was found to elicit robust neutralizing antibodies in vivo. This designed sE1E2 can both provide insights into the determinants of native E1E2 assembly and serve as a platform for production of E1E2 for future structural and vaccine studies, enabling rational optimization of an E1E2-based antigen.
- Subjects :
- Models, Molecular
Viral Hepatitis Vaccines
0301 basic medicine
Protein Conformation
Gene Expression
Hepacivirus
Protein Engineering
Virus
Epitope
Tetraspanin 28
Epitopes
Mice
03 medical and health sciences
Immunogenicity, Vaccine
0302 clinical medicine
Viral Envelope Proteins
Viral envelope
Antigen
Glycoprotein complex
Animals
Humans
Neutralizing antibody
Furin
Multidisciplinary
biology
Vaccination
Antibodies, Monoclonal
Biological Sciences
Hepatitis C Antibodies
Antibodies, Neutralizing
Hepatitis C
Virology
Recombinant Proteins
Transmembrane domain
030104 developmental biology
Solubility
biology.protein
Receptors, Virus
Female
030211 gastroenterology & hepatology
Protein Multimerization
Epitope Mapping
Protein Binding
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....fe760342749e3d6c9b7f0db94fc3a9c1