Elucidating the host and viral determinants of treatment response in chronic hepatitis B

About This Grant

Project Summary Hepatitis B virus (HBV) chronically infects more than 250 million people and puts them at risk of developing liver cirrhosis and hepatocellular carcinoma. Every year over 800,000 people die due to HBV-related complications. The natural history of chronic HBV infection goes through several phases characterized by the presence of HBV e antigen (eAg) in serum. Most chronically infected individuals are initially eAg positive and later in life become eAg negative, which is associated with enrichment of viral mutations in the basal core promoter (BCP) and precore (PC) regions. Some individuals spontaneously control HBV and lose surface antigen, termed a functional cure. There are two approved types of medications for chronic HBV infection, nucleoside analogs (NA) and interferon-alpha (IFNα). While NA are well-tolerated, work across genotypes and irrespective of eAg status, they rarely lead to a functional cure. By contrast, IFNα therapy can functionally cure a subset (<10%) of patients but comes with significant adverse effects. It has long been appreciated that IFNα responses differ by eAg status and by HBV genotype. eAg positive patients are cured at a higher rate than eAg negative patients, and HBV genotype A (HBV-A) is more susceptible to IFNα than HBV-D. In a recent North American trial studying the effects of NA withdrawal after four years of therapy a small number of eAg positive HBV subgenotype A2 (HBV- A2) patients responded very well, with 67% functional cure rate in the monotherapy group and 100% cure in the NA + IFNα group. This contrasted with HBV-A2 eAg negative and HBV-A1 or HBV-D patients, none of whom where cured. These results suggest that eAg positive HBV-A2 is highly susceptible to currently approved therapies and offers an opportunity to understand the mechanisms by which IFNα leads to a cure. IFNα has broad antiviral mechanisms and can induce hundreds of human interferon-stimulated genes, depending on the pathogen and cell type. The antiviral mechanisms of IFNα against HBV are poorly understood. They involve the induction of interferon-stimulated genes in hepatocytes, the liver cell type infected by HBV, as well as effects on immune cells. We here aim to use eAg positive HBV-A2 to understand the antiviral mechanisms of IFNα in human hepatocytes. Our recent advances in launching HBV infection from recombinant DNA and our primary human hepatocyte cell cultures and animal models can now be exploited and combined with multiomics approaches and novel CRISPR validation tools. These systems will be used to investigate the antiviral mechanism of an interferon-stimulated host gene against HBV-A2 and other genotypes, map regions of patient- derived HBV-A2 genomes conferring susceptibilty to IFNα, and compare IFNα responses between isogenic wild type and PC and BCP region HBV-A2 mutants. In all, these studies combine expertise from multiple fields with the goal of advancing insights into the antiviral mechanisms of IFNα, which may aid in the development of more effective therapies against chronic HBV.