Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0023890 (
cirrhosis
)
42,195
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Chronic infection by hepatitis B virus (HBV) is associated with high risks of liver fibrosis,
cirrhosis
and hepatocellular carcinoma. In mouse models of HBV persistence,
interleukin 21
(
IL-21
) has been identified as a potent inducer of viral clearance. Strict hepatotropism makes recombinant HBV (rHBV) vectors ideal for liver-targeting gene delivery. Previously, we established an rHBV vector termed 5c3c, which is highly replicative by itself, but requires HBV envelope proteins provided
in trans
to produce virions. 5c3c-based rHBV virions are capable of delivering cargo gene expression driven by HBV Sp1 promoter into infected hepatocytes. In this work, we explore the feasibility of using 5c3c-derived rHBV for liver-specific delivery of
IL-21
as treatment of chronic HBV infection.
Methods:
5c3c-derived rHBV replicons harboring mouse or human
IL-21
genes (termed 5c3c-mIL-21 and 5c3c-hIL-21 respectively) were constructed and then tested for the production of rHBV virions
in vitro
and
in vivo
. 5c3c-mIL-21's anti-HBV effects were determined in chronic HBV mouse model. Furthermore, superinfection by rHBV virions was analysed using HBV-infected HepG2/NTCP cells and human liver chimeric mice.
Results:
5c3c-mIL-21 and 5c3c-hIL-21 were efficiently replicative and produced enveloped virions when provided with envelope proteins, both
in vitro
and
in vivo
. In mouse model of HBV persistence,
IL-21
expressed from injected 5c3c-mIL-21 replicon induced complete viral clearance. 5c3c-mIL-21 and 5c3c-hIL-21 virions could infect HepG2/NTCP cells and engender sustained
IL-21
expression. Most importantly,
IL-21
-expressing rHBV virions could superinfect HBV-infected HepG2/NTCP cells and human hepatocytes in human liver chimeric mice, and engender sustained
IL-21
expression and rHBV production.
Conclusion:
These data suggest the high potential of 5c3c-derived
IL-21
-expressing rHBV as a novel therapeutic against chronic HBV infection.
...
PMID:Characterization of IL-21-expressing recombinant hepatitis B virus (HBV) as a therapeutic agent targeting persisting HBV infection. 3237 34
