Abstract
The paucity of animal models that simulate the replication of the hepatitis B virus (HBV) is an impediment to advancing new anti-viral treatments. The work reported here employed recombinant adeno-associated viruses (AAVs) to model HBV subgenotype A1 and subgenotype D3 replication in vitro and in vivo. Infection with subgenotype A1 is endemic to parts of sub-Saharan Africa, and it is associated with a high risk of hepatocellular carcinoma. Recombinant AAV serotype 2 (AAV2) and 8 (AAV8) vectors bearing greater-than-genome-length sequences of HBV DNA from subgenotype A1 and D3, were produced. Transduced liver-derived cultured cells produced HBV surface antigen and core antigen. Administration of AAV8 carrying HBV subgenotype A1 genome (AAV8-A1) to mice resulted in the sustained production of HBV replication markers over a six-month period, without elevated inflammatory cytokines, expression of interferon response genes or alanine transaminase activity. Markers of replication were generally higher in animals treated with subgenotype D3 genome-bearing AAVs than in those receiving the subgenotype A1-genome-bearing vectors. To validate the use of the AAV8-A1 murine model for anti-HBV drug development, the efficacy of anti-HBV artificial primary-microRNAs was assessed. Significant silencing of HBV markers was observed over a 6-month period after administering AAVs. These data indicate that AAVs conveniently and safely recapitulate the replication of different HBV subgenotypes, and the vectors may be used to assess antivirals’ potency.
Highlights
Hepatitis B virus (HBV) is a small, enveloped virus of the family Hepadnaviridae.Infection of the liver by HBV may cause acute or chronic infection, and chronic carriers are at a high risk for cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]
HBV sequences of subgenotype A1 and D3 into single-stranded associated viruses (AAVs), such that the HBV genome sequence was flanked by inverted terminal repeats (ITR) (Figure 1a)
Subgenotype A1 or D3 sequences resulted in significant HBV surface antigen (HBsAg) secretion at 48 and 72 h post-transfection (Supplementary Figure S1)
Summary
Hepatitis B virus (HBV) is a small, enveloped virus of the family Hepadnaviridae.Infection of the liver by HBV may cause acute or chronic infection, and chronic carriers are at a high risk for cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]. Two billion people have been infected with HBV, and 296 million are currently chronically infected. The genotypes, and in some instances subgenotypes, have distinct geographical distributions, manifesting in different clinical consequences and responses to therapy. In South Africa, where approximately two and a half million people are chronically infected with HBV [6], subgenotype A1 prevails [7]. This subgenotype is associated with a high risk for HCC [8]. Several HBV subgenotypes exist with different disease manifestations, responses to therapy and geographical distributions [5,10]
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