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Hepatitis B: future curative strategies.

Bertoletti A, Rivino L - Curr. Opin. Infect. Dis. (2014)

Bottom Line: In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response.These new therapeutic approaches have mainly been tested in animal models.In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile.

View Article: PubMed Central - PubMed

Affiliation: aProgram Emerging infectious Diseases, Duke-NUS Medical School, Singapore bSingapore Institute for Clinical Sciences, A*STAR, Singapore cSchool of Immunity and Infection, College of Medical and Dental Science, University of Birmingham, Edgbaston Birmingham, UK.

ABSTRACT

Purpose of review: Hepatitis B virus (HBV) causes a large proportion of chronic liver disease worldwide. The limited efficiency of current treatments based on the use of nucleotide/nucleoside analogues or interferon-alpha requires the development of new therapeutic tools for the treatment of chronic HBV. We summarize the most recent therapeutic strategies designed to directly target HBV-infected hepatocytes or to restore antiviral immunity during chronic HBV infection.

Recent findings: Novel therapies directly target HBV-infected hepatocytes by inducing covalently closed circular DNA degradation or by inhibiting HBV entry or the expression of viral proteins. In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response.

Summary: These new therapeutic approaches have mainly been tested in animal models. In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile.

Show MeSH

Related in: MedlinePlus

Schematic representation of new hepatitis B virus therapeutic strategies. (a) Direct inhibition (DNA/RNA/Protein). (b) Boosting HBV-specific adaptive immunity. (c) Boosting innate immunity. Ab, antibody; APC, antigen-presenting cell; CAR, chimeric antigen receptors; cccDNA, covalently closed circular DNA; DC, dendritic cell; HBV, hepatitis B virus; IFN, interferon; LTβ, lymphotoxin-β; NTCP, sodium-taurocholate cotransporting polypeptide; TALEN, transcription activator-like effector nucleases; TLR, toll-like receptor.
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Figure 1: Schematic representation of new hepatitis B virus therapeutic strategies. (a) Direct inhibition (DNA/RNA/Protein). (b) Boosting HBV-specific adaptive immunity. (c) Boosting innate immunity. Ab, antibody; APC, antigen-presenting cell; CAR, chimeric antigen receptors; cccDNA, covalently closed circular DNA; DC, dendritic cell; HBV, hepatitis B virus; IFN, interferon; LTβ, lymphotoxin-β; NTCP, sodium-taurocholate cotransporting polypeptide; TALEN, transcription activator-like effector nucleases; TLR, toll-like receptor.

Mentions: In the last few years, new strategies aimed at improving cccDNA clearance have been developed (Fig. 1a). A recent study proposed lymphotoxin-β-receptor (LTβR) activation of HBV-infected cells as a therapeutic alternative capable of mediating degradation of cccDNA in infected hepatocytes without hepatotoxicity [14▪▪]. Similarly to IFN-α, LTβR (lymphotoxin beta receptor) signalling was shown to induce the upregulation of cytidine deaminases of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of proteins that can specifically target the cccDNA for deamination and degradation. These findings highlight the potential use of nuclear deaminases for eradication of cccDNA expression. However, therapeutic LTβR activation needs to be carefully evaluated in patients as LTβR agonists could potentially trigger apoptosis, inflammation and HCC [15].


Hepatitis B: future curative strategies.

Bertoletti A, Rivino L - Curr. Opin. Infect. Dis. (2014)

Schematic representation of new hepatitis B virus therapeutic strategies. (a) Direct inhibition (DNA/RNA/Protein). (b) Boosting HBV-specific adaptive immunity. (c) Boosting innate immunity. Ab, antibody; APC, antigen-presenting cell; CAR, chimeric antigen receptors; cccDNA, covalently closed circular DNA; DC, dendritic cell; HBV, hepatitis B virus; IFN, interferon; LTβ, lymphotoxin-β; NTCP, sodium-taurocholate cotransporting polypeptide; TALEN, transcription activator-like effector nucleases; TLR, toll-like receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4232294&req=5

Figure 1: Schematic representation of new hepatitis B virus therapeutic strategies. (a) Direct inhibition (DNA/RNA/Protein). (b) Boosting HBV-specific adaptive immunity. (c) Boosting innate immunity. Ab, antibody; APC, antigen-presenting cell; CAR, chimeric antigen receptors; cccDNA, covalently closed circular DNA; DC, dendritic cell; HBV, hepatitis B virus; IFN, interferon; LTβ, lymphotoxin-β; NTCP, sodium-taurocholate cotransporting polypeptide; TALEN, transcription activator-like effector nucleases; TLR, toll-like receptor.
Mentions: In the last few years, new strategies aimed at improving cccDNA clearance have been developed (Fig. 1a). A recent study proposed lymphotoxin-β-receptor (LTβR) activation of HBV-infected cells as a therapeutic alternative capable of mediating degradation of cccDNA in infected hepatocytes without hepatotoxicity [14▪▪]. Similarly to IFN-α, LTβR (lymphotoxin beta receptor) signalling was shown to induce the upregulation of cytidine deaminases of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) family of proteins that can specifically target the cccDNA for deamination and degradation. These findings highlight the potential use of nuclear deaminases for eradication of cccDNA expression. However, therapeutic LTβR activation needs to be carefully evaluated in patients as LTβR agonists could potentially trigger apoptosis, inflammation and HCC [15].

Bottom Line: In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response.These new therapeutic approaches have mainly been tested in animal models.In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile.

View Article: PubMed Central - PubMed

Affiliation: aProgram Emerging infectious Diseases, Duke-NUS Medical School, Singapore bSingapore Institute for Clinical Sciences, A*STAR, Singapore cSchool of Immunity and Infection, College of Medical and Dental Science, University of Birmingham, Edgbaston Birmingham, UK.

ABSTRACT

Purpose of review: Hepatitis B virus (HBV) causes a large proportion of chronic liver disease worldwide. The limited efficiency of current treatments based on the use of nucleotide/nucleoside analogues or interferon-alpha requires the development of new therapeutic tools for the treatment of chronic HBV. We summarize the most recent therapeutic strategies designed to directly target HBV-infected hepatocytes or to restore antiviral immunity during chronic HBV infection.

Recent findings: Novel therapies directly target HBV-infected hepatocytes by inducing covalently closed circular DNA degradation or by inhibiting HBV entry or the expression of viral proteins. In addition, immunotherapeutic approaches may boost HBV-specific T-cell responses or stimulate the intrahepatic innate response.

Summary: These new therapeutic approaches have mainly been tested in animal models. In humans, therapeutic strategies could be tailored to different chronic HBV patients in relation to their clinical and virological disease profile.

Show MeSH
Related in: MedlinePlus