Selective depletion of HBV-infected hepatocytes by class A capsid assembly modulators requires high levels of intrahepatic HBV core protein

作者：Dmytro Kornyeyev, Zhijuan Song, Stacey Eng, Cameron M. Soulette, Ricardo Ramírez, Jennifer Tang, Qin Yue, Raju Subramanian, Shiva Zaboli, Christina Moon, Jane Tam, Jens Brodbeck, Abhishek Aggarwal, Lauri Diehl, Simon P. Fletcher, Anastasia Hyrina, Meghan Holdorf, Dara Burdette · 发表于：Antimicrobial Agents and Chemotherapy · 年份：2024 · DOI：10.1128/aac.00420-24 · 被引用次数：6 · 研究领域：Hepatitis B Virus Studies、Hepatitis C virus research、Liver Disease Diagnosis and Treatment

Capsid assembly mediated by hepatitis B virus (HBV) core protein (HBc) is an essential part of the HBV replication cycle, which is the target for different classes of capsid assembly modulators (CAMs). While both CAM-A ("aberrant") and CAM-E ("empty") disrupt nucleocapsid assembly and reduce extracellular HBV DNA, CAM-As can also reduce extracellular HBV surface antigen (HBsAg) by triggering apoptosis of HBV-infected cells in preclinical mouse models. However, there have not been substantial HBsAg declines in chronic hepatitis B (CHB) patients treated with CAM-As to date. To investigate this disconnect, we characterized the antiviral activity of tool CAM compounds in HBV-infected primary human hepatocytes (PHHs), as well as in HBV-infected human liver chimeric mice and mice transduced with adeno-associated virus-HBV. Mechanistic studies in HBV-infected PHH revealed that CAM-A, but not CAM-E, induced a dose-dependent aggregation of HBc in the nucleus which is negatively regulated by the ubiquitin-binding protein p62. We confirmed that CAM-A, but not CAM-E, induced HBc-positive cell death in both mouse models via induction of apoptotic and inflammatory pathways and demonstrated that the degree of HBV-positive cell loss was positively correlated with intrahepatic HBc levels. Importantly, we determined that there is a significantly lower level of HBc per hepatocyte in CHB patient liver biopsies than in either of the HBV mouse models. Taken together, these data confirm that CAM-As...