Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure

Abstract

Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.

CRISPR-Cas9 Targeting of Hepatitis B Virus Covalently Closed Circular DNA Generates Transcriptionally Active Episomal Variants

“…The CRISPR-Cas9 system is easily reprogrammable, and different DNA sequences can be targeted by redesigning the guide RNAs (gRNAs) ( 10 ). Though several studies evaluated the potential of gene-editing approaches to target the HBV genome, the fate of the edited cccDNA molecules and their biological functions have not been evaluated ( 11 , 12 ). Furthermore, the possibility that Cas9 could target HBV DNA replicative intermediates exhibiting the target sequence as double-stranded DNA (dsDNA), such as protein-free rcDNA, rather than cccDNA directly or before cccDNA establishment, has not been excluded.…”

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

“…Despite available well-functioning vaccines and inhibitors targeting various steps of the virus life cycle (recently reviewed in [95]), hepatitis B-virus (HBV), an enveloped DNA virus, remains a major health problem [96]. HBV replication depends on a step catalyzed by error-prone reverse transcriptase, and has therefore been included among RNA viruses with low fidelity polymerases in this review.…”

Improving Therapeutic Vaccination against Hepatitis B—Insights from Preclinical Models of Immune Therapy against Persistent Hepatitis B Virus Infection

“…However, HBV cccDNA is sensitive to the anti-viral activity of cytokines, such as interferons and lymphotoxin [10], but these mediators fail to eliminate all HBV cccDNA from infected hepatocytes for reasons that remain to be discovered [6,11,12]. Current direct antiviral treatment options were recently addressed in expert reviews [13][14][15].…”