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Stem Cell-Derived Viral Ag-Specific T Lymphocytes Suppress HBV Replication in Mice
Published on: September 25, 2019
Activating the innate immune response to counter chronic hepatitis B virus infection
Camilla Lamb1, Patrick Arbuthnot1
1a Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences , University of the Witwatersrand , Johannesburg , South Africa.
Insights
Activating the innate immune system shows promise for treating chronic hepatitis B virus (HBV) infection. Therapies targeting Toll-like receptors (TLRs) and lymphotoxin-beta receptors may eradicate HBV, offering a potential cure.
Area of Science:
- Hepatology
- Immunology
- Virology
Background:
- Chronic hepatitis B virus (HBV) infection is a global health issue, leading to cirrhosis and liver cancer.
- Current treatments for HBV have limited efficacy in eradicating the virus.
- Developing therapies to eliminate HBV replication intermediates is a critical research priority.
Purpose of the Study:
- To explore the therapeutic potential of activating the innate immune response for treating chronic HBV infection.
- To evaluate small molecule stimulators of Toll-like receptors (TLRs) and lymphotoxin-beta receptor agonists as antiviral strategies.
- To assess the feasibility of eliminating HBV covalently closed circular DNA (cccDNA) for a potential cure.
Main Methods:
- Investigated small molecule TLR agonists (e.g., GS-9620, a TLR7 agonist) for their ability to inhibit HBV replication in animal models and human trials.
- Examined the use of lymphotoxin-beta receptor agonists to trigger APOBEC-mediated deamination and degradation of HBV cccDNA.
- Reviewed existing literature on gene therapy and immunomodulation for HBV treatment.
Main Results:
- Small molecule TLR agonists demonstrated inhibition of HBV and woodchuck hepatitis virus replication in preclinical models.
- GS-9620, a TLR7 agonist, was found to be well-tolerated in early-stage human clinical trials.
- Activation of the innate immune response, including via lymphotoxin-beta receptor agonists, showed potential for HBV eradication by targeting cccDNA.
Conclusions:
- Innate immune activation represents a promising therapeutic strategy for chronic hepatitis B.
- Eliminating HBV cccDNA is a key goal for achieving a functional cure for chronic HBV infection.
- Combination therapies involving immunomodulation may significantly contribute to the global control and eradication of HBV.
Introduction:
Chronic infection with hepatitis B virus (HBV) is endemic to several populous parts of the world, where resulting complicating cirrhosis and hepatocellular carcinoma occur commonly. Licensed drugs to treat the infection have limited curative efficacy, and development of therapies that eliminate all replication intermediates of HBV is a priority. Areas covered: The recent demonstration that the activation of the innate immune response may eradicate HBV from infected hepatocytes has a promising therapeutic application. Small molecule stimulators of Toll-like receptors (TLRs) inhibit replication of woodchuck hepatitis virus in woodchucks and HBV in chimpanzees and mice. Early stage clinical trials using GS-9620, a TLR7 agonist, indicate that this candidate antiviral is well tolerated in humans. Using an alternative approach, triggering the innate immune response with agonists of lymphotoxin-β receptor caused efficient APOBEC-mediated deamination and degradation of viral covalently closed circular DNA. Expert opinion: Eliminating HBV cccDNA from infected individuals would constitute a cure, and has become the focus of intensive research that employs various therapeutic approaches, including gene therapy. Immunomodulation through innate immune activation shows promise for the treatment of chronic infection of HBV (CHB) and, used in combination with other therapeutics, may contribute to the global control of infections and ultimately to the eradication of HBV.
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