The new front‐line in hepatitis B/D research: Identification and blocking of a functional receptor

T reatment for chronic hepatitis B (CHB) over the last two decades has drawn on immune-based interferon-a (IFN-a) or direct-acting antiviral agents in the category of nucleos(t)ide analogues (NAs). Over this time, various combinations of these two treatment approaches have been submitted to trials, but with disappointing gains over the respective monotherapies. This has been offset in part by the positive impact that these therapies have had on the lives of patients with CHB in significantly reducing the risk of development of progressive liver disease and hepatocellular carcinoma. Equally dramatic has been the observed reversal of hepatitis B virus (HBV)-associated fibrosis and cirrhosis, with a commensurate decrease in the need for liver transplantation. Unfortunately, current therapies remain less than ideal. Pegylated IFN-a, despite a finite duration of therapy, has a substantial adverse event profile, and patients struggle to stay on treatment for the full 48 weeks. In contrast, NAs require long-term therapy, perhaps lifelong, in order to achieve the benefits outlined above. This is because the NAs have little effect on the virological goal of eradicating HBV covalently closed circular DNA (cccDNA) from infected hepatocytes and markers of active viral replication, including HBV DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg), leading to a key endpoint for achieving cure through HBsAg antibody (anti-HBs) seroconversion. Recent mathematical modeling has estimated the time to HBsAg loss/anti-HBs seroconversion with the existing NAs at over 30 years. Thus, problems of compliance and resistance, even with the most potent NAs, will almost certainly emerge. In the human immunodeficiency virus (HIV)-1/ acquired immune deficiency syndrome (AIDS) treatment armamentarium, there are over 20 drugs from six major classes directed against multiple targets in the HIV life cycle, including entry, enzyme action, assembly, and release. These drugs are used very effectively in synergistic combinations that form the basis of successful highly active antiretroviral therapy regimens. From this level of control of active HIV replication, patients can be expected to have a normal lifespan, and HIV-AIDS researchers are preparing new strategies to eradicate HIV from the infected host. This goal has been given the highest priority by national funding agencies. In contrast, in the hepatitis B treatment arena, more drugs targeted to other parts of the viral life cycle are desperately needed if HBV control and eradication are to be achieved. Fortunately, the news from the front line in the battle against HBV and its satellite virusoid, hepatitis delta virus (HDV), is encouraging. In this issue of HEPATOLOGY, two papers from the University Hospital Heidelberg group led by Stephan Urban report some critical next steps. The investigators focused on early events, both in vitro and in vivo, in the HBV life cycle, namely attachment followed by specific binding to a receptor usually expressed on the cell surface. These steps account for the striking host species specificity (humans, higher primates, and Tupaia belangeri) and tissue tropism (liver) of HBV. Earlier studies from this group and their collaborators demonstrated that myristoylated pre-S1 peptides efficiently blocked and thereby inhibited HBV infection in in vitro models of primary Tupaia hepatocytes and cultures of differentiated HepaRG cells. By using these model systems, the specific receptor binding site of HBV has been narrowed down to a critical region of the pre-S1 protein spanning amino acid (aa) residues 9-18, with aa residues 29-48 enhancing infection inhibition, whereas aa residues 19-28 and 1-8 were dispensable. Interestingly, HDV, which replicates in HBV-infected hepatocytes and packages its ribonucleoprotein in the HBV envelope, can also be inhibited by these acylated HBV pre-S derived peptides (e.g., preS/ 2-48myr) with the same specificity. This shows that HDV has at least one step in common with HBV for Abbreviations: aa, amino acid; AIDS, acquired immune deficiency syndrome; anti-HBs, HBsAg antibody; cccDNA, covalently closed circular DNA; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HDV, hepatitis delta virus; HIV, human immunodeficiency virus; IFN-a, interferon-a; NA, nucleos(t)ide analogue; NTCP, sodium taurocholate cotransporting polypeptide. Address reprint requests to: Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn Street, North Melbourne, Victoria 3051, Australia. E-mail: stephen.locarnini@mh.org.au; fax: þ61-39342-2666. CopyrightVC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26292 Potential conflict of interest: Dr. Locarnini consults for Gilead and BristolMyers Squibb.