# Structural analysis of HCV E1E2 glycoproteins

> **NIH NIH U19** · STANFORD UNIVERSITY · 2023 · $209,444

## Abstract

ABSTRACT – PROJECT 4
Despite extensive research efforts to understand the biology of hepatitis C virus (HCV), it remains a major human 
pathogen without a vaccine. In addition, there is a remarkable absence of information regarding the structure of 
the virion and organization of its component proteins. We intend to use our extensive structural biology 
experience with the related flaviviruses, to focus on determining the structure of the viral glycoproteins, the virus 
particle, and complexes of potent neutralizing antibodies bound to the surface glycoproteins. This project will rely 
heavily on and interact extensively with Project 1 to interrogate the structure and provide guidance into the 
features of the glycoproteins that are important for eliciting broad and potent neutralizing antibodies. Iterative 
analysis and re-engineering of the E1E2 glycoproteins will be conducted to guide the antibody component of a 
dual B and T cell HCV vaccine, the focus of this U19 proposal. This specific project will use three aims to 
determine the structure of the E1E2 heterodimer, the virus particle, and neutralizing antibody Fabs bound to the 
glycoproteins. Based on biophysical and immunological assays, computational modeling and structure analyses, 
the E1E2 glycoproteins will be engineered to present epitopes that elicit strong neutralizing and broadly reactive 
antibodies and minimize the presentation of decoy non-productive epitopes. Furthermore, the organization of 
the glycoproteins and the structure of the virus particle will be determined. The tools of molecular virology, 
biophysics, computational modeling, x-ray crystallography and cryo-electron microscopy will be used to produce 
atomic-level details of the epitope landscape of HCV. The gained structural information will be utilized to design 
novel antigens in Project 1, determine the structures of designed immunogens experimentally in Project 4 and 
tested in vivo in Projects 1, 2 and 3. We will guide Project 1 at various times during the project to allow them to 
utilize the optimal E1E2 immunogen for studies in guinea pigs and, ultimately, a lead candidate for an optimized 
E1E2 immunogen for nonhuman primate studies. This information will be invaluable in deciphering the nature of 
neutralizing antibodies and their mechanisms of action against HCV and will shed light on the assembly and 
entry of hepatitis C virions.

## Key facts

- **NIH application ID:** 10797243
- **Project number:** 5U19AI159840-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Richard J. Kuhn
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $209,444
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797243

## Citation

> US National Institutes of Health, RePORTER application 10797243, Structural analysis of HCV E1E2 glycoproteins (5U19AI159840-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10797243. Licensed CC0.

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