Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Abstract

Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

The Yin and the Yang of Treatment for Chronic Hepatitis B—When to Start, When to Stop Nucleos(t)ide Analogue Therapy

“…The development of curative treatments for HBV infection would be a major advance for the field. There are multiple antiviral and immunomodulatory treatment candidates in pre-clinical and clinical development [84]. Whether these approaches succeed, and if successful what the time to market will be, is hard to predict but likely at least 5-10 years away.…”

Targeting Host Innate and Adaptive Immunity to Achieve the Functional Cure of Chronic Hepatitis B

“…In CHB patients, HBV-specific T cell responses are characterized by functional exhaustion, premature deletion, and weak virus-specific T cell responses that impede viral clearance, while the presence of HBV-specific-antibody producing B cells and functional HBV-specific T cells ultimately determines the outcome of HBV infection. These concepts have been analyzed in several previous reviews [ 56 , 121 , 122 , 123 , 124 , 125 ]. T cells exhausted by persistent exposure to high concentrations of antigen load, particularly HBsAg, are characterized by the hierarchical loss of effector T cell functions; upregulation of multiple inhibitory receptors known as checkpoint proteins, including PD-1, cell immunoglobulin mucin-3 (TIM-3), CD160, CTLA-4, LAG-3, and T-cell immunoreceptor with Ig and ITIM domain (TIGIT); impaired fatty acid oxidation (FAO); reactive oxygen species (ROS) overproduction; mitochondrial dysfunction; and defective effector T cells [ 28 , 125 , 126 , 127 ].…”

Immuntherapien zur Behandlung der chronischen Hepatitis-B-Virusinfektion – eine Übersicht unter besonderer Berücksichtigung von CAR-T-Zellen

“…Ein weiterer Ansatz (TherVacB) basiert auf einer Prime-Boost-Strategie unter Verwendung von HBsAg-und HBcAg-Partikeln für das Priming, gefolgt von einer weiteren Immunisierung (Boost) durch einen MVA-basierten Vektor, der core-, preS-, S-und pol-spezifische Antigene codiert. TherVacB B ist derzeit noch in der präklinischen Phase [49].…”

“…die Kombination mit Checkpointinhibitoren zu erwägen und eine Verminderung der Menge an zirkulierenden HBV-Antigenen vor der Immunisierung anzustreben. Eine wesentliche Bedeutung wird hierbei auch der Identifizierung von Wirtsfaktoren zukommen, welche für T-Zellerschöpfung prädisponieren [44,49,51]. Die in diesem Artikel enthaltenen Bilder und sonstiges Drittmaterial unterliegen ebenfalls der genannten Creative Commons Lizenz, sofern sich aus der Abbildungslegende nichts anderes ergibt.…”

“…die Kombination mit Checkpointinhibitoren zu erwägen und eine Verminderung der Menge an zirkulierenden HBV-Antigenen vor der Immunisierung anzustreben. Eine wesentliche Bedeutung wird hierbei auch der Identifizierung von Wirtsfaktoren zukommen, welche für T‑Zellerschöpfung prädisponieren [ 44 , 49 , 51 ].…”