Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B

Abstract

Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

“…AtMBCs in CHB patients have decreased survival, proliferation, and cytokine production and cannot develop into antibody-producing plasma cells, resulting in reduced humoral immune responses. Vanwolleghem et al [ 68 ] discovered that HBcAg binding to B cells leads to increased expression of inhibitory receptors FcRL4 and FcRL5, dysfunctional phenotypes, and suppressed B cell proliferation (Table 1 ) and activation via B cell receptor and TLR signaling[ 68 , 84 ].…”

Inhibition of Alpha Interferon-Induced miR-873 Negatively Affects the Hepatitis B Virus Expression

“…Chronic hepatitis B (CHB), which is triggered by HBV infection, remains a major public health issue. WHO estimates that 296 million people were living with CHB infection in 2019, with 1.5 million new infections each year [1]. Currently, treatment of CHB consists mainly of pegylated alpha interferon (IFN-α) and nucleotide analogs (NAs) [2].…”

The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis

“…A great advantage of this model is the stepwise progression of experimentally WHV-induced liver disease in an immunologically intact host that is inherently susceptible to a highly molecularly and pathogenically HBV-compatible virus. This infection model has been applied for basic research, preclinical evaluations of new anti-viral and anti-cancerous agents, and assessment of novel immunological approaches against CHB and HBV-associated HCC [9][10][11][12][13].…”