In brief

Immune cells that recognize a specific peptide sequence of the hepatitis B virus help control long term infections.

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Why hepatitis B hits some harder than others

30 Sep 2019

A gene variant more common among East Asians is responsible for milder symptoms and better outcomes during hepatitis B infection.

A cat-and-mouse game is constantly taking place between the body’s immune system and infectious microbes. In particular, a class of immune cells known as CD8+ T cells plays a key role in keeping viral infections in check by destroying infected cells and releasing antiviral molecules.

However, certain viruses like the hepatitis B virus (HBV) can linger for long periods of time in the body. Some people respond to such chronic infections with severe liver inflammation, while others do not display symptoms and become carriers of the virus, often with low or undetectable viral loads. It is unclear how such different outcomes arise.

In this study, a team of scientists led by Evan Newell and Yang Cheng from the Singapore Immunology Network (SIgN) demonstrated that in HBV-infected patients with the A*11:01 allele, which is more common among East Asians, recovery and long term suppression of HBV was associated with higher frequencies of T cells that target a critical sequence of amino acids in the virus.

“We combined the power of two cell profiling techniques—mass cytometry and highly multiplexed combinatorial peptide-MHC tetramer staining—to comprehensively and simultaneously probe more than 500 T cell epitopes in a single patient sample,” said Cheng, explaining that the epitopes referred to here are HBV protein sequences to which T cells bind. Their strategy also allowed them to investigate more than 20 behaviors and functions of T cells.

The team found larger numbers of CD8+ T cells in A*11:01-positive patients with acutely resolved infections, and that these T cells bind specifically to the HBVcore169 peptide. The HBVcore169 peptide is part of the inner shell of HBV surrounding the virus genome.

“Analysis of surface markers on these T cells revealed that they have long-term memory and a diverse array of inhibitory receptors. With this information, we were able to construct a disease progression timeline that predicts the disease outcome using high-dimensional trajectory analysis and machine learning-aided modeling,” said Cheng. These findings were subsequently validated in a study involving patients undergoing antiviral therapy—the T cell responses in patients matched what the authors had predicted.

The researchers propose that their findings will facilitate the development of immunotherapies such as engineered T cells against HBV. Also, since the study focused on patients with the A*11:01 allele, the findings are highly relevant to patients in Singapore and the Asia Pacific region.

Going forward, the team plans to investigate how these HBV-targeting T cells can eliminate liver tumors associated with HBV infection.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and the Genome Institute of Singapore (GIS).

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Cheng, Y., Zhu, Y. O., Becht, E., Aw, P., Chen, J. et al. Multifactorial heterogeneity of virus-specific T cells and association with the progression of human chronic hepatitis B infection. Science Immunology 4(32), eaau6905 (2019) | article

About the Researcher

Yang Cheng is a Research Fellow working in Evan Newell’s lab at the Singapore Immunology Network (SIgN), A*STAR. He completed his undergraduate studies in Soochow University, Taiwan, and underwent training in immunology at Academia Sinica, Taiwan. He subsequently studied T cell responses in type 1 diabetes and chronic viral infection in Matthias von Herrath’s lab in La Jolla Institute, US, before obtaining his MSc degree at University College London, UK, and PhD degree at SIgN. His research interests include liver cancer and the immunological response to chronic HBV infection.

This article was made for A*STAR Research by Wildtype Media Group