# Structural analysis of HCV E1E2 glycoproteins

> **NIH NIH U19** · STANFORD UNIVERSITY · 2022 · $308,106

## 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:** 10409764
- **Project number:** 5U19AI159840-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Richard J. Kuhn
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $308,106
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409764

## Citation

> US National Institutes of Health, RePORTER application 10409764, Structural analysis of HCV E1E2 glycoproteins (5U19AI159840-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10409764. Licensed CC0.

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