In Vivo Model Systems for Hepatitis B Virus Research

Abstract

Hepatitis B virus (HBV) affects more than 257 million people globally, resulting in progressively worsening liver disease, manifesting as fibrosis, cirrhosis, and hepatocellular carcinoma. The exceptionally narrow species tropism of HBV restricts its natural hosts to humans and non-human primates, including chimpanzees, gorillas, gibbons, and orangutans. The unavailability of completely immunocompetent small-animal models has contributed to the lack of curative therapeutic interventions. Even though surrogates allow the study of closely related viruses, their host genetic backgrounds, immune responses, and molecular virology differ from those of HBV. Various different models, based on either pure murine or xenotransplantation systems, have been introduced over the past years, often making the choice of the optimal model for any given question challenging. Here, we offer a concise review of in vivo model systems employed to study HBV infection and steps in the HBV life cycle or pathogenesis.

Human Organs-on-Chips for Virology

“…The inability to reproduce the complexity of the liver environment using conventional in vitro models – that usually include only primary human hepatocytes (PHHs) – limits the ability to study host–pathogen interactions of such diseases [ 28 , 35 ]. In addition, most animal models are not susceptible to HBV infection or cannot be infected by HBV directly due to its narrow host range [ 35 , 36 ]. However, liver chip platforms have provided new opportunities to study viral hepatitis in a more physiological environment.…”

Refining Host-Pathogen Interactions: Organ-on-Chip Side of the Coin

“…Defining host–pathogen interactions in viral hepatitis and associated liver disease has so far been limited by the narrow host range of the hepatitis B virus (HBV) and the inability to reproduce the complexity of the liver environment using conventional methods [ 48 ]. The application of organ chips to HBV research began with a rat liver sinusoid chip system to study viral replication [ 49 ], which was followed by a human source model via incorporation of primary human hepatocytes (PHHs) and reported expression of hepatitis B core antigen (HBcAg) as well as cellular secretion of HBV DNA post HBV infection [ 50 ].…”

Modeling Hepatotropic Viral Infections: Cells vs. Animals

“…The lack of an appropriate platform for a better understanding of the molecular basis and the absence of reliable models to identify novel therapeutic agents for a targeted treatment are the two major obstacles for launching efficient clinical protocols in different types of viral hepatitis [ 1 , 2 ]. The hepatotropic viruses A, B, C, D, and E, are the most common causes of viral infections that can lead to liver failure.…”

“…Studying hepatotropic viruses in vivo is limited because most of them are species-specific. For instance, HBV and HCV infect only humans, tree shrews, and some nonhuman primates [ 2 , 12 ]. Thus, the most promising approach to study human hepatotropic viruses is using genetically modified animals.…”