Mapping Determinants of Hepatitis C Virus E1/E2 Transmembrane Interactions Using Intergenotypic Chimeras

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Hepatitis C virus (HCV) poses a significant global health challenge with no available preventive vaccine.
• The E1/E2 envelope glycoproteins complex is crucial for viral entry, but its assembly and stability mechanisms are not fully understood.

Purpose of the Study:

• To investigate the role of E1/E2 transmembrane (TM) regions in HCV infectivity.
• To explore the impact of swapping TM domains between different HCV genotypes on viral function.

Main Methods:

• Constructed chimeric HCV recombinants by swapping C-terminal TM domains (TME1, TME2, TME1E2) of E1/E2 glycoproteins between different genotypes (H77, S52, J6).
• Assessed infectivity of TM-swap chimeras and analyzed adaptive mutations following serial passaging.
• Investigated the effect of extending TME1 swaps and including internal E1 TM regions (iTME1).

Main Results:

• Most TM-swap chimeras exhibited reduced infectivity.
• Serial passaging led to partial infectivity recovery through adaptive mutations in E1/E2, including TM, stem, and iTME1 regions.
• Extending TME1 swaps improved infectivity in some cases, while iTME1 inclusion abolished it.

Conclusions:

• HCV E1/E2 transmembrane regions and associated membrane-proximal domains significantly influence viral infectivity.
• Functional interactions exist between membrane-associated regions and ectodomains of E1/E2.
• Findings are relevant for developing E1/E2-based HCV vaccines.