Activating the innate immune response to counter chronic hepatitis B virus infection

ABSTRACT

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.

KEYWORDS:

• Cccdna
• cytokines
• HBV
• immunotherapy
• interferon
• Toll like receptor

Article highlights

• Chronic HBV infection is associated with an immunologically-complex hepatic microenvironment exhibiting characteristics of a chronic inflammatory state as well as HBV-specific tolerogenesis.

• Many aspects of HBV immunopathogenesis remain to be fully elucidated, largely as a result of a lack of convenient animal models that accurately recapitulate the infection in humans.

• Immunomodulating drugs, specifically those that act to stimulate the innate immune system, show promise for the treatment of CHB either alone or in combination with classical antivirals such as NUCs.

• GS-9620, an exogenous ligand of TLR7, has proven antiviral potential in chimpanzee and woodchucks, as well as in human patients. GS-9620 has proceeded on to clinical studies while other TLR and STING agonists are currently in preclinical development.

• Though controversial, the more recent development of antibodies targeting the LTβR has been shown to initiate APOBEC-mediated clearance of cccDNA from infected cells.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors laboratory is financially supported by the South African Medical Research Council, the South African Poliomyeltis Research Foundation, Johnson & Johnson Innovation and the South African National Research Foundation. The financial support provided by Johnson & Johnson Innovation is provided to carry out work aimed at advancing therapy for hepatitis B virus infection.