Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.
نویسندگان
چکیده
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.
منابع مشابه
Virology. Response to Comment on "Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA".
Chisari et al. challenge our central conclusion that the hepatitis B virus (HBV) persistent form, the covalently closed circular DNA (cccDNA), is degraded in a noncytotoxic and specific fashion in the nucleus of infected hepatocytes. Specificity of the assays used, exclusion of cell division or death, and activity of APOBEC3 deaminases in the nucleus, however, were addressed in the paper.
متن کاملVirology. Comment on "Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA".
Lucifora et al. (Research Articles, 14 March 2014, p. 1221) report that the hepatitis B virus (HBV) transcriptional template, a long-lived covalently closed circular DNA (cccDNA) molecule, is degraded noncytolytically by agents that up-regulate APOBEC3A and 3B. If these results can be independently confirmed, they would represent a critical first step toward development of a cure for the 400 mi...
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ورودعنوان ژورنال:
- Science
دوره 343 6176 شماره
صفحات -
تاریخ انتشار 2014