A nucleosome switch primes Hepatitis B Virus infection

Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The first viral protein expressed, HBx, induces degradation of a host silencing factor to facilitate infection. However, the relationship between cccDNA chromatin and early HBx transcription remains poorly understood. Establishing reconstituted viral minichromosomes, we found that nucleosomes in cccDNA drive HBx transcription. We corroborated these findings in cells and further showed that the chromatin destabilizing drug CBL137 inhibits infection in hepatocytes. Our results shed new light on a long-standing paradox and represent a novel therapeutic avenue for the treatment of chronic HBV. ### Competing Interest Statement R.E.S. is on the scientific advisory boards of Miromatrix Inc. and Lime Therapeutics and is a speaker and consultant for Alnylam Inc. All other authors declare that they have no competing interests.