R01AI175800

Role of Antibodies in Hepatitis E Virus Infection - Summary

The goal of the proposed study is to better understand the role of antibodies in HEV infection and determine if antibodies can prevent or cure chronic Hepatitis E Virus (HEV) infection.

HEV infections are usually self-limited, but the infections frequently persist when the immune system is compromised. If left untreated, they can lead to serious liver disease.

HEV exists in two distinct virion forms: naked virions (NHEV) that are shed into feces and mediate virus transmission between hosts, and quasi-enveloped HEV (EHEV) virions that circulate in the bloodstream and mediate virus spread between cells.

The EHEV particles lack viral antigens on their surface, thus they are resistant to circulating HEV-specific antibodies.

We previously showed that EHEV particles enter cells via a novel entry mechanism that involves lysosomal degradation of the viral envelope.

Our recent data show that HEV-specific IgG, but not IgM, effectively block EHEV-mediated spread in cell culture.

Our central hypothesis is that antibodies neutralize EHEV intracellularly by preventing virus uncoating in the endosome/lysosome where the viral membrane degrades.

Antibodies generated by natural HEV infection and vaccination with truncated HEV capsid proteins (CP) are highly protective against HEV infection, while anti-HEV antibody titers are usually low in patients with chronic HEV infection.

Thus, antibodies may have the potential to prevent or treat chronic HEV infection.

Despite these encouragements, there are several significant roadblocks.

First, the C terminus of the HEV CP, which is not present in the current vaccine and the fecal virus, is intact in the EHEV particles.

This is important since structural modeling suggests that the presence of the C terminus of CP significantly alters the surface structure of the virion, which likely makes vaccine-induced antibodies less effective against EHEV.

Second, our recent work indicates that HEV produces a capsid decoy that is secreted from infected cells in a large quantity and interferes with antibody-mediated neutralization.

Third, antibody uptake by hepatocytes is an inefficient process.

Here we propose to overcome these obstacles.

Aim 1 will test the hypothesis that antibodies targeting virions with intact CP will block EHEV-mediated spread more efficiently.

We will determine the structure of authentic HEV virions with intact or cleaved CP and assess if antibodies targeting virions with intact CP neutralize EHEV more efficiently.

We will also determine if glycoengineered antibodies with enhanced lysosomal targeting neutralize EHEV more efficiently.

Aim 2 will test the hypothesis that neutralizing antibodies that do not bind or bind poorly to the decoy will block HEV spread more efficiently.

We will also determine the structure of the CP decoy in complex with antibodies by cryo-EM to gain a better understanding of the evasion mechanism by the decoy.

The completion of the proposed work will provide novel insights into the role of antibodies in HEV infection and inform strategies to prevent or cure chronic HEV infection.

Research Institute At Nationwide Children's Hospital

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93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Columbus, Ohio 432052664 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 285% from $864,317 to $3,331,268.