Functional cure of hepatitis B requires silencing covalently closed circular and integrated hepatitis B virus DNA

Ghany, Marc G.; Lok, Anna S.

doi:10.1172/jci163175

Cited by 11 publications

(1 citation statement)

References 18 publications

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“…There has not been a substantial HBsAg reduction reported to date in CHB patients treated with either RG7907 or GLS4, despite both compounds strongly reduce serum HBV DNA and HBV RNA levels ( 18 – 20 ). This is likely due, at least in part, to the production of HBsAg from HBV-integrated cells, which do not express HBc and therefore are not expected to be susceptible to CAM-A treatment ( 34 , 35 ). Our study provides an additional explanation for the discrepancy in preclinical and clinical efficacy of CAM-A.…”

Section: Discussionmentioning

confidence: 99%

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

Kornyeyev,

Song,

Eng

et al. 2024

Antimicrob Agents Chemother

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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 have a unique secondary mechanism with the potential to kill HBc-positive hepatocytes. However, this secondary mechanism appears to require higher intrahepatic HBc levels than is typically observed in CHB patients, thereby limiting the therapeutic potential.

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