Crafty Hepatitis E Virus Uses Decoy to Evade Immune System

Researchers find a related protein cloaking the virus has differences that could become treatment targets

(From the June 2018 issue of Research Now)

A protein that doctors use as a marker of hepatitis E virus (HEV) infection is not directly involved in the virus lifecycle but acts as a decoy drawing away antibodies, helping HEV evade the immune system and thrive, researchers in the Center for Vaccines and Immunity report in Proceedings of the National Academy of Sciences (PNAS).

Until now, it was unclear how ORF2 protein found in the blood of patients is produced or that it is different from the ORF2 protein cloaking the virus shell, or capsid.

The capsid protein, which the researchers labeled ORF2C, shares features and capabilities with the decoy protein found in blood serum, which they labeled ORF2S. But their differences may provide targets for therapies, the researchers say.

HEV infects about 20 million people annually, mostly in underdeveloped countries.

“In certain cases, HEV can cause a high mortality rate, especially in pregnant women,” says Zongdi Feng, PhD, a principal investigator at The Research Institute’s Center for Vaccines and Immunity and senior author of the study. “In developed countries, the most important clinical problem is chronic infection in the immunosuppressed. The infection can result in liver fibrosis within two years, which is much faster than hepatitis B and C.”

“There is currently no therapy for the immunosuppressed,” says Xin Yin, PhD, a postdoctoral research fellow at the center and lead author. “We could possibly use an antibody that specifically binds to the capsid protein and would not be absorbed by the serum protein for treating the immunosuppressed.”

The ORF2S protein is found in high numbers freely circulating in the blood serum of infected patients and the liquid covering HEV-infected cell cultures in the lab.

By analyzing ORF2 protein produced in cultures, Drs. Feng and Yin and colleagues found the vast majority of the protein in the covering liquid was not associated with the infectious virus. Though similar, it appears to have differences in size, structure and some chemistry from ORF2C.

The researchers also found that the gene that directs production of ORF2S is the same gene that directs production of ORF2C; the start codon incorrectly thought to be the starting point for ORF2C actually initiates ORF2S. ORF2C is initiated 15 codons downstream. The 15 more amino acids in ORF2S create a signal sequence that causes the virus to secrete the protein, and in far higher numbers than ORF2C.

The researchers suggest the secreted proteins act as decoys to keep the immune system busy without attacking the actual virus.

“Production of the serum protein may be how the virus copes with the host and persists,” Dr. Feng says. “We need to take a more detailed look in an animal model.”

Drs. Feng and Yin are collaborating with other researchers to identify the similarities and differences in the structure of the two proteins. Their research is funded by Nationwide Children’s, the National Institutes of Health and the American Association for the Study of Liver Disease Foundation. They are also seeking continuing funding to investigate how the serum protein operates during the infection process and the implications.

Citation: Yin X, Ying D, Lhomme S, Tang Z, Walker CM, Xia N, Zheng Z, Feng Z. Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection. Proceedings of the National Academy of Sciences. 2018 May 1;115(18):4773-4778. doi: 10.1073/pnas.1721345115. Epub 2018 Apr 18.