Gene Therapy for Chronic HBV—Can We Eliminate cccDNA?

Bloom, Kristie; Maepa, Mohube Betty; Ely, Abdullah; Arbuthnot, Patrick

The critical limitation of licensed therapeutics is their inability to reliably achieve a virological cure [3] . While NAs inhibit posttranscriptional stages of viral replication, they do not target the stable episomal covalently closed circular DNA (cccDNA). This key HBV replication intermediate forms a minichromosome in the nucleus of hepatocytes [8] [9] [10] , and may undergo epigenetic modifications [11] [12] [13] . The hepatitis B X protein (HBx) plays a role in stabilizing cccDNA by inactivating components of the structural maintenance of chromosomes (SMC) complex [14] . The cccDNA associates with host transcription factors and viral proteins to enable viral gene expression and replication. Associations with factors regulating methylation or heterochromatin formation may also render cccDNA inactive, and lead to persistent latent or occult HBV infections. Cessation or interruption of antiviral therapy, development of viral escape mutants, or immunodeficiency could all lead to reactivation of HBV replication, highlighting the need for cccDNA-specific therapies. This review focuses on recent advances aimed at generating HBV-targeting designer nucleases, epigenetic modifications to the viral DNA and nucleic acid-based immune modulation to treat chronic HBV infection.