Background & Aims
Current hepatitis B virus (HBV) management is challenging as treatment with nucleos(t)ide
analogues needs to be maintained indefinitely and because interferon (IFN)-α therapy
is associated with considerable toxicity. Previously, we showed that linking IFNα
to apolipoprotein A-I generates a molecule (IA) with distinct antiviral and immunostimulatory
activities which lacks the hematological toxicity of IFNα.
Methods
Here, we analyse the antiviral potential of an adeno-associated vector encoding IFNα
fused to apolipoprotein A-I (AAV-IA) in comparison to a vector encoding only IFNα
(AAV-IFN) in two animal models of chronic hepadnavirus infection.
Results
In HBV transgenic mice, we found that both vectors induced marked reductions in serum
and liver HBV DNA and in hepatic HBV RNA but AAV-IFN caused lethal pancytopenia. Woodchucks
with chronic hepatitis virus (WHV) infection that were treated by intrahepatic injection
of vectors encoding the woodchuck sequences (AAV-wIFN or AAV-wIA), experienced only
a slight reduction of viremia which was associated with hematological toxicity and
high mortality when using AAV-wIFN, while AAV-wIA was well tolerated. However, when
we tested AAV-wIA or a control vector encoding woodchuck apolipoprotein A-I (AAV-wApo)
in combination with entecavir, we found that AAV-wApo-treated animals exhibited an
immediate rebound of viral load upon entecavir withdrawal while, in AAV-wIA-treated
woodchucks, viremia and antigenemia remained at low levels for several weeks following
entecavir interruption.
Conclusions
Treatment with AAV-IA is safe and elicits antiviral effects in animal models with
difficult to treat chronic hepadnavirus infection. AAV-IA in combination with nucleos(t)ide
analogues represents a promising approach for the treatment of HBV infection in highly
viremic patients.
Graphical abstract
Graphical Abstract
Abbreviations:
AAV (adeno-associated virus), AAV-IFN (adeno-associated vector encoding mouse interferon alpha), AAV-IA (adeno-associated vector encoding mouse interferon alpha fused to apolipoprotein A-I), AAV-Luc (adeno-associated vector encoding luciferase), AAV-wApo (adeno-associated vector encoding woodchuck apolipoprotein A-I), AAV-wIFN (adeno-associated vector encoding woodchuck interferon alpha), AAV-wIA (adeno-associated vector encoding woodchuck interferon alpha fused to apolipoprotein A-I), apoA-I (apolipoprotein A-I), HBV (hepatitis B virus), HBVTg (HBV transgenic mice), CHB (chronic hepatitis B), ELISA (enzyme-linked immunosorbent assay), EMCV (encephalomyocarditis virus), ETV (entecavir), IFNα (interferon-α), IA (interferon fused to apolipoprotein A-I), ISG15 (interferon-stimulated-gene 15), NAs (nucleoside/nucleotide analogues), 2′-5′ OAS (2′-5′-oligoadenylate synthetase), USP18 (ubiquitin specific peptidase 18), vg (viral genomes), WHV (woodchuck hepatitis virus), WHsAg (woodchuck hepatitis virus surface antigen)Keywords
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Article info
Publication history
Published online: March 14, 2015
Accepted:
February 23,
2015
Received in revised form:
February 13,
2015
Received:
September 15,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
