Specific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA
By J. Lucifora, Yuchen Xia, F. Reisinger, Ke Zhang, Daniela Stadler, Xiaoming Cheng, M. Sprinzl, H. Koppensteiner, Z. Makowska, T. Volz and 14 more. Science, 2014
878 citations recorded by the source corpus.
Clearance of Chronic Virus The family of mRNA-editing enzymes, APOBEC, restricts hepatitis B virus (HBV) replication. Lucifora et al. (p. 1221, published online 20 February; see the Perspective by Shlomai and Rice) provide evidence that specific APOBECs mediate the anti-HBV effects of host cytokines, which in turn apparently induce nuclear deaminase activity without damaging host cells. Thus, there may be potential in these findings for developing a therapeutic route to curing chronic HBV infection. Cytokine induction renders viral DNA vulnerable and eliminates infection. Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-α treatment can clear HBV but is limited by systemic side effects. We describe how interferon-α can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-β receptor activation as a therapeutic alternative. Interferon-α and lymphotoxin-β receptor activation up-regulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases—for example, by lymphotoxin-β receptor activation—allows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B.
Subfields: Epidemiology, Immunology, Virology
View Paper: https://www.semanticscholar.org/paper/6cf49d65a643aa7e2d64c49d0bcc99b9cb411251
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Citations in the corpus
- Molecular Biology of Hepatitis B Virus Infection (2015, positive): “A more recent cell culture study presented evidence that interferon alpha, gamma and other cytokines can induce APOBEC3, which then targets cccDNA for depurination and degradation, and might explain non-cytolytic clearance (Lucifora et al., 2014).”
- Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update (2015, background): “HBV-infected cells [650], and cccDNA-specific transcription activator-like effector nucleases (TALENs) [651].”