Abstract
Immunity against hepatitis B virus (HBV) infection is complex and not entirely understood so far, including the decisive factors leading to the development of chronic hepatitis B. This lack of a mechanistic understanding of HBV-specific immunity is also caused by a limited number of suitable animal models. Here, we describe the generation of a recombinant adenovirus expressing an HBV 1.3-overlength genome linked to luciferase (Ad-HBV-Luc) allowing for precise analysis of the quantity of infected hepatocytes. This enables sensitive and close-meshed monitoring of HBV-specific CD8 T cells and the onset of anti-viral immunity in mice. A high dose of Ad-HBV-Luc developed into chronic hepatitis B accompanied by dysfunctional CD8 T cells characterized by high expression of PD1 and TOX and low expression of KLRG1 and GzmB. In contrast, a low dose of Ad-HBV-Luc infection resulted in acute hepatitis with CD8 T cell-mediated elimination of HBV-replicating hepatocytes associated with elevated sALT levels and increased numbers of cytotoxic HBV-specific CD8 T cells. Thus, the infectious dose was a critical factor to induce either acute self-limited or chronic HBV infection in mice. Taken together, the new Ad-HBV-Luc vector will allow for highly sensitive and time-resolved analysis of HBV-specific immune responses during acute and chronic infection.
Highlights
Hepatitis B virus (HBV) infections are still considered a major global health problem, accounting for 296 million chronically infected people worldwide in 2019 [1]
To study the immune response against HBV in mice, we developed an adenoviral shuttle system transferring HBV 1.3-overlength genomes into murine hepatocytes
We added a click beetle green luciferase linked by a P2A sequence at the second truncated HBVcore antigen (HBcAg) open reading frame (Ad-HBV-Luc)
Summary
Hepatitis B virus (HBV) infections are still considered a major global health problem, accounting for 296 million chronically infected people worldwide in 2019 [1]. HBV infection of adults results in viral persistence in only 5% of cases [2,3,4]. The decisive factors determining chronic disease outcome are currently still poorly understood and may be associated with the organ of infection, the liver, and its role in regulating immune responses. The liver is regarded as a lymphoid organ, which is unique in its microenvironment and cell composition [5,6]. In the liver, the induction of anti-viral. T cell immunity as well as the induction of tolerance mechanism may take place depending on the total amount and quality of immune stimulation during the infection [7,8,9,10]. Chronic hepatitis B is characterized by weak and progressively exhausted HBV-specific
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