A global scientific strategy to cure hepatitis B

Abstract

Chronic hepatitis B virus (HBV) infection is a global public health challenge on the same scale as tuberculosis, HIV, and malaria. The International Coalition to Eliminate HBV (ICE-HBV) is a coalition of experts dedicated to accelerating the discovery of a cure for chronic hepatitis B. Following extensive consultation with more than 50 scientists from across the globe, as well as key stakeholders including people affected by HBV, we have identified gaps in our current knowledge and new strategies and tools that are required to achieve HBV cure. We believe that research must focus on the discovery of interventional strategies that will permanently reduce the number of productively infected cells or permanently silence the covalently closed circular DNA in those cells, and that will stimulate HBV-specific host immune responses which mimic spontaneous resolution of HBV infection. There is also a pressing need for the establishment of repositories of standardised HBV reagents and protocols that can be accessed by all HBV researchers throughout the world. The HBV cure research agenda outlined in this position paper will contribute markedly to the goal of eliminating HBV infection worldwide.

Figure 1:. The hepatitis B virus replication cycle

Following viral entry via binding of the preS1 domain of the large envelope protein to the sodium-taurocholate co-transporting polypeptide (NTCP) receptor on the hepatocyte plasma membrane, the viral and cellular membranes fuse to release the nucleocapsid, which is transported into the cell nucleus.The nucleocapsid then disassembles to release its cargo of partially double-stranded genomic viral DNA. The host DNA repair machinery converts the incoming DNA to covalently closed circular DNA (cccDNA) molecules that are packaged into chromatin-like minichromosomes by histone and non-histone proteins,^, whereupon it acts as the HBV transcriptional template and long-lived reservoir in the hepatocyte nucleus.¹⁰ The 3∙2 kb HBV genome is organised into four overlapping but frame-shifted open-reading frames encoding the core protein (HBcAg, nucleocapsid); polymerase (P); the precore protein, which is processed to secreted hepatitis B e antigen (HBeAg); hepatitis B surface antigens (HBsAg, consisting of the large, medium, and small envelope proteins); and the X protein (HBx). A number of virus-encoded promoter and enhancer elements promote transcription of five major mRNAs, namely pregenomic (pgRNA, also the core mRNA), precore mRNA, preS1 and preS2/S mRNA, and HBx mRNA, which are translated into the aforementioned seven viral proteins. The pgRNA is encapsidated with P and reverse transcribed into DNA. Following viral DNA synthesis mature nucleocapsids are either packaged with envelope proteins to be exported as infectious virions, or recycled back to the nucleus for cccDNA replenishment. DSL-DNA=double-stranded linear DNA. RC-DNA=relaxed circular DNA.

Figure 2:. Current and future HBV virological and immunological targets that will be necessary for treatment and cure of chronic hepatitis B

Adapted from reference . CpAMs/CAMs=core protein allosteric modulators/capsid assembly modulators. CAR =chimeric antigen receptor. cccDNA=covalently closed circular DNA. IL=interleukin. IFN-α=interferon-α. KC=Kupffer cell. NK=natural killer cell. NKT=natural killer T cell. pDC=plasmocytoid dendritic cell. RC DNA=relaxed circular DNA.

Figure 3:. Mechanisms of CD8+ T-cell failure and potential targets for curative immunotherapeutic approaches in the setting of chronic hepatitis B

HBsAg=hepatitis B surface antigen. IL=interleukin. MDSC=myeloid-derived suppressor cells. NK=natural killer. TCR=T-cell receptor. TGF=transforming growth factor.