Mechanism of Hepatitis B Virus

Millions of people are chronically infected with HBV worldwide despite the use of an effective vaccine. Those infected are at a high risk of developing liver cancer. Although current therapeutic regimens exist that can efficiently suppress viral replication of HBV, the virus has a unique replication strategy that enables the virus to persist within infected hepatocytes and eventually cause a relapse of viral activity within the infected individual. Progress in understanding HBV replication and the development of more effective therapeutic strategies aiming to achieve sustained viral control is hindered.

Covalently Closed Circular DNA and Chronic Infection

Covalently closed circular DNA that is involved with viral production of the virus is not yet identified. The virological and immunological mechanisms that prevent virus eradication and lead to the development of chronic infection are still poorly understood. A new strategy that scientists are trying is to predict the chance to achieve off-treatment sustained viral response (SVR) after PEG-IFN treatment. By successfully completing this and combining sustained HBV-DNA suppression off-treatment with reduced HBsAG levels, which are measured quantitatively during treatment.

Chimpanzees as Experimental Models

The chimpanzee is the only host fully susceptible to HBV infection due to the similarities in their immune systems in comparison to that of humans. This is demonstrated by the induction of acute infection and hepatitis after injection of serum from human hepatitis B virus carriers. Although chimpanzees do not usually suffer from chronic liver disease, they are the only primates known to develop a cellular response and slew of symptoms when infected by HBV, similar to those observed in humans. For this reason, researchers have relied heavily on chimpanzees to study the pathogenesis of acute HBV infection. These primates have played an essential role in the development of a safe and effective vaccine which will neutralize HBV specific antibodies and also determine the half-life of circulating HBV virions as to predict the breakdown of these molecules and assess patients over time. The vaccine has also been tested against various mutations of the Hepatitis B virus, including drug resistant pathogens by rechallenging the chimpanzees either with homologous or heterologous viruses. Because sequential liver biopsies can be obtained throughout the course of infection, chimpanzees represent an extremely valuable infection system for prospective analysis of intrahepatic virological changes and immune responses. These studies are primarily used to study the relationship between host and virus providing evidence that hepatocellular injury caused by HBV is predominantly afflicted by the host’s own immune system and then in acute, self-limited infection, the CD8 T cell responses to HBV proteins are stronger than expected. While the HBV specific CD8 T cell response plays a fundamental role in destroying the invading virus, CD4 T cell depletion experiments showed that these cells do not directly participate in viral clearance, though they may contribute to induce and maintain B cell and CD8 T cell responses in chimpanzees.

Limitations of Using High Primates

Productive infection by HBV is limited to human and chimpanzees. The limitations of being forced to use high primates, such as chimpanzees, as an experimental host instead of humans has caused an obvious slow down and possible stalling of information in the experiment, and therefore has impeded our understanding of the HBV virus and how it works. This, in turn, has slowed the process of creating antiviral pharmaceuticals to combat the problem.

Surrogate Systems for Research

Numerous surrogate systems based on in vitro transfection or transduction of the HBV-DNA genome have successfully been developed to gain knowledge of the HBV replication mechanisms and to evaluate the effect of drugs targeting specific steps of HBV life cycle. The discovery of a cell line in part susceptible of HBV infection has greatly expanded the experimental possibilities for studying the early steps of infection.