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How a Cancer-Causing Virus Evades the Immune Response

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Scientists have discovered a mechanism by which a cancer-causing virus can escape the body’s immune response. The research – led by Florida State University’s (FSU) Department of Biological Science and the Institute of Molecular Biophysics – is published in the Proceedings of the National Academy of Science.

Cancer-causing viruses

There are several viruses linked to human cancers, including human papillomavirus, Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Kaposi sarcoma–associated herpes virus (KSHV), to name a few examples. KSHV most commonly causes cancer in patients that are immunocompromised.

“The human immune system is normally very effective in the recognition of viral infection and the subsequent launching of antiviral defenses,” said Dr. Qian Yin, assistant professor in biological science. “Viral RNA and DNA can be detected by the host immune sensors to trigger potent antiviral immune responses. Therefore, in order for viruses to establish infection and persist in the host, viruses have evolved elaborate mechanisms to evade these host immune responses.” What these mechanisms are, and how we can perhaps manipulate them to treat cancer, is a focus of Yin’s research.

Enzyme sensor for detecting foreign viral DNA

An enzyme known as cyclic GMP-AMP synthase – or cGAS – is one of the immune system’s most important sensors for detecting foreign viral DNA. It binds and blocks the DNA to trigger antiviral and pro-inflammatory immune responses, stopping or slowing the virus in its tracks. cGAS is therefore one of the key targets for cancer-causing viruses like KSHV.

Dr. Fanxiu Zhu, professor of biological sciences and a specialist in KSHV research, discovered a KSHV protein that is capable of inhibiting cGAS – named KicGAS – in 2015. “While previous research showed that this KSHV protein inhibits cGAS enzymatic activity, how it does its job remained unclear,” said Zhu.

In the new study, Zhu and colleagues adopted structural biology approaches to decipher the crystal structure of this protein. “The simple repeating units of the viral protein form a long polymeric chain, explaining how it binds to DNA more efficiently and providing insight into its competitive inhibition of cGAS activity,” said Zhu. “The unexpected polymeric nature of this viral protein separates it from other known viral relatives, which also hints at co-evolution between the viruses and their hosts.”

“Discovering the underlying mechanisms by which KSHV inhibits cGAS is essential to understanding how viruses cause human cancers and how evasion of the host immune responses contributes to the development of tumors,” said Dr. Debipreeta Bhowmik, postdoctoral scholar and another study co-author. “Cancer cells usually actively replicate their DNA with a less rigid quality control system, and abnormal DNAs from cancer cells are now known to be sensed by cGAS in immune cells to trigger anti-tumor immunity to destroy cancer cells.”

The researchers emphasize that an understanding of the KicGAS protein’s structure may help to inform drug design for antiviral therapeutics against KSHV, and potentially other related viruses.

Reference: Bhowmik D, Tian Y, Wang B et al. Structural basis of higher order oligomerization of KSHV inhibitor of cGAS. PNAS. 2022;119(33):e2200285119. doi: 10.1073/pnas.2200285119.

This article is a rework of a press release issued by Florida State University. Material has been edited for length and content.