Hepatitis B Virus Adaptation to the CD8+ T Cell Response: Consequences for Host and Pathogen

Abstract

Chronic viral hepatitis infections are a major public health concern, with an estimated 290 million individuals infected with hepatitis B virus (HBV) globally. This virus has been a passenger in human populations for >30,000 years, and remains highly prevalent in some settings. In order for this endemic pathogen to persist, viral adaptation to host immune responses is pre-requisite. Here, we focus on the interplay between HBV infection and the CD8+ T cell response. We present the evidence that CD8+ T cells play an important role in control of chronic HBV infection and that the selective pressure imposed on HBV through evasion of these immune responses can potentially influence viral diversity, chronicity, and the outcome of infection, and highlight where there are gaps in current knowledge. Understanding the nature and mechanisms of HBV evolution and persistence could shed light on differential disease outcomes, including cirrhosis and hepatocellular carcinoma, and help reach the goal of global HBV elimination by guiding the design of new strategies, including vaccines and therapeutics.

Data from an electronic health informatics pipeline to describe clearance dynamics of Hepatitis B surface antigen (HBsAg) and e-Antigen (HBeAg) in chronic HBV infection

“…HBeAg clearance occurred over a median period of 54 weeks, substantially more quickly than HBsAg clearance which was documented over a median period of 157 weeks, perhaps indicating different underlying mechanisms at play (34, 37, 39). Further studies are needed to determine the relevant immune responses that underpin this clearance, and to identify possible triggers for clearance.…”

“…Our dataset corroborates prior literature in confirming that treatment is not pre-requisite for clearance, and that immunological clearance of HBsAg and HBeAg can occur independently of antiviral therapy (Fig 1C) (23, 36). There are multiple host and viral factors influencing outcome during CHB infection including host factors such as age, obesity, gender and diabetes along with genetic variations in CD8+ T-cell responses (mediated by HLA genotype), T-cell receptor antagonism and viral escape mutations (37, 38).…”

“…We included all the parameters in our dataset in multivariable analysis, based on existing biological reasons to believe them likely to be relevant. Specifically, age at first HBsAg test is known to be associated with HBsAg clearance, sex and ethnicity could indicate diffrences in host genetics and immune response, and HBeAg status is a known marker of disease severity (20, 26, 37). Code used for this analysis is available in the attached HBsAg_Final_Analysis.html file included in the supplementary information.…”

Checkpoint Inhibitors and Therapeutic Vaccines for the Treatment of Chronic HBV Infection

“…HBV has a relatively low mutation rate and because the open reading frames of the viral genome partially overlap, there are constraints to the number of amino acid substitutions that are viable. Nonetheless, genetic diversity consistent with immune pressure is observed during chronic infection: mainly within the core and envelope protein, but also to a lesser degree in the polymerase protein (62)(63)(64). In sum, there are multiple mechanisms contributing to T cell dysfunction during chronic HBV infection.…”

Molecular, Evolutionary, and Structural Analysis of the Terminal Protein Domain of Hepatitis B Virus Polymerase, a Potential Drug Target

“…For example, mutations in the RT domain of HBV Pol (the target of antivirals) have been shown to affect HBsAg (the antigenic target of the HBV vaccine) and vice versa. This can cause functional changes in viral fitness, immune interactions, and drug resistance [90][91][92]. However, due to the lack of TP domain sequencing data, no information has been published about ORF overlap between the TP domain of HBV Pol and HBcAg/HBeAg.…”