# Mechanism for spread of a quasi-enveloped hepatotropic virus

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $470,475

## Abstract

Summary
Hepatitis E virus (HEV), an enterically transmitted virus, exists either as naked virions that are shed in the feces
or quasi-enveloped virions that circulate in the blood. The quasi-envelopment of HEV facilitates noncytolytic
release of virus from infected cells. However, the lack of viral envelope proteins raises question about mechanism
for HEV spread and the role of antibodies in natural infection. HEV infects ~20 million people annually and causes
significant morbidity and mortality. Persistent HEV infection in immunocompromised individuals can lead to rapid
progression of liver fibrosis. Currently there are no FDA-approved diagnostics and HEV-specific therapies. Our
long-term goal is to unravel the functional role(s) of this unusual envelopment in the virus life cycle and
pathogenesis for the purpose of identifying novel targets for therapeutic intervention. The overall objective of this
project is to understand the role of the quasi-envelopment in HEV spread and how it affects antibody-mediated
neutralization. The viral ORF3 protein is known to play a key role in HEV envelopment. Our preliminary data
suggest that ORF3 is subjected to regulation by palmitoylation to mediate virion release. In addition, we found
evidence that neutralizing antibodies block HEV spread in cells that have already established infection. Our
central hypothesis is that ORF3-mediated quasi-envelopment is required for HEV release into the bloodstream
and into the bile (then shed into feces), and quasi-enveloped HEV particles mediate spread with the liver via a
novel entry mechanism that is susceptible to post-entry neutralization by antibodies. We will test this hypothesis
in polarized hepatocyte cell culture and in human liver chimeric mice. Aim 1 will define the role of palmitoylation
of ORF3 in its cellular localization and function in virus release. Aim 2 will define the cellular requirements and
role of ORF3 in HEV spread. Aim 2 will also define the role and mechanism of antibodies in blocking HEV spread.
The expected outcomes of the proposed research are novel insights into the spread mechanism for a quasi-
enveloped virus, and may have implications for other non-enveloped viruses such as hepatitis A, poliovirus, and
enteroviruses that also become quasi-enveloped at certain stages of their life cycle. This work will fill gaps in our
understanding of the quasi-envelopment processes and how it influences virus spread, pathogenesis and
immunity.

## Key facts

- **NIH application ID:** 9990681
- **Project number:** 5R01AI139511-03
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Zongdi Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $470,475
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990681

## Citation

> US National Institutes of Health, RePORTER application 9990681, Mechanism for spread of a quasi-enveloped hepatotropic virus (5R01AI139511-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9990681. Licensed CC0.

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