Hepatitis B virus rigs the cellular metabolome to avoid innate immune recognition
Li Zhou, Rui He, Peining Fang, Mengqi Li, Haisheng Yu, Qiming Wang, Yi Yu, Fubing Wang, Yi Zhang, Aidong Chen, Nanfang Peng, Yong Lin, Rui Zhang, Mirko Trilling, Ruth Broering, Mengji Lu, Ying Zhu, Shi Liu
Abstract
Glucose metabolism and innate immunity evolved side-by-side. It is unclear if and how the two systems interact with each other during hepatitis B virus (HBV) infections and, if so, which mechanisms are involved. Here, we report that HBV activates glycolysis to impede retinoic acid-inducible gene I (RIG-I)-induced interferon production. We demonstrate that HBV sequesters MAVS from RIG-I by forming a ternary complex including hexokinase (HK). Using a series of pharmacological and genetic approaches, we provide in vitro and in vivo evidence indicating that HBV suppresses RLR signaling via lactate dehydrogenase-A-dependent lactate production. Lactate directly binds MAVS preventing its aggregation and mitochondrial localization during HBV infection. Therefore, we show that HK2 and glycolysis-derived lactate have important functions in the immune escape of HBV and that energy metabolism regulates innate immunity during HBV infection.