Infection and Drug Resistance (Oct 2020)
cccDNA Maintenance in Chronic Hepatitis B – Targeting the Matrix of Viral Replication
Abstract
Maura Dandri,1,2 Joerg Petersen3 1Department of Internal Medicine, University Medical Center Hamburg – Eppendorf, Hamburg, Germany; 2German Center for Infection Research (DZIF), Hamburg-Luebeck-Borstel-Riems Site, Germany; 3Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, University of Hamburg, Hamburg, GermanyCorrespondence: Maura DandriDepartment of Internal Medicine, University Medical Center Hamburg – Eppendorf, Martinistr. 52, Hamburg D - 20246, GermanyTel + 49 40 7410 52949Fax + 49 40 7410 57232Email [email protected] PetersenLiver Unit, IFI Institute at the Asklepios Klinik St Georg Hamburg, Haus L, Lohmühlenstr. 5, Hamburg 20099, GermanyTel +49 40 284 07 60 0Fax +49 40 284 07 60 222Email [email protected]: Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma, despite an effective prophylactic vaccine and well-tolerated and effective oral antivirals. Both the incapacity of the immune system to clear hepatitis B virus (HBV) infection and the unique replication strategies adopted by HBV are considered key determinants of HBV chronicity. In this regard, the formation of the HBV DNA minichromosome, the covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, is essential not only for the production of all viral proteins but also for HBV persistence even after long-term antiviral therapy. Licensed polymerase inhibitors target the HBV reverse transcriptase activity, control the disease with long-term therapy but fail to eliminate the cccDNA. Consequently, the production of viral RNAs and proteins, including the hepatitis B surface antigen (HBsAg), is not abolished. Novel therapeutic efforts that are in the pipeline for early clinical trials explore novel targets and molecules. Such therapeutic efforts focus on achieving a functional cure, which is defined by the loss of HBsAg and undetectable HBV DNA levels in serum. Since a true cure of HBV infection requires the elimination of the cccDNA from infected cells, comprehension of the mechanisms implicated in cccDNA biogenesis, regulation and stability appears necessary to achieve HBV eradication. In this review, we will summarize the state of knowledge on cccDNA metabolism, focusing on insights suggesting potential weak points of the cccDNA that may be key for the development of therapeutic approaches and design of clinical trials aiming at lowering cccDNA loads and activity.Keywords: hepatitis B virus, cccDNA, animal models, human liver chimeric mice, antiviral therapy
