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.
Highlights
The rate of newly acquired hepatitis B virus (HBV) infection is well-controlled by prophylaxis with conventional hepatitis B surface antigen (HBsAg) vaccines; the vast reservoir of nearly 300 million chronic HBV-infected individuals worldwide still represents a serious threat to humans, leading to up to about 900,000 deaths every year [1,2,3]
A recent ex vivo study showed that HBV-specific CD4+ T cells isolated from individuals with HB e-antigen (HBeAg)-negative HBV infection could be activated by OX40 stimulation combined with PD-L1 blockade, with remarkably increased IFN-γ and IL-21 production in vitro
Twelve-week GS-9620 administration in chronic hepatitis B (CHB) patients with HBV well suppressed by nucleos(t)ide analogs (NUCs) resulted in increased T- and NK-cell responses and decreased NK cell-mediated T cell inhibition, while no significant decrease in serum HBsAg levels was achieved
Summary
The rate of newly acquired hepatitis B virus (HBV) infection is well-controlled by prophylaxis with conventional HBsAg vaccines; the vast reservoir of nearly 300 million chronic HBV-infected individuals worldwide still represents a serious threat to humans, leading to up to about 900,000 deaths every year [1,2,3]. Enhanced HBsAg/HBcAg-specific cellular immune responses lead to significantly reduced serum HBsAg levels without liver injury in HBV transgenic mice [85]. In mice with persistent HBV replication, the VSV-MHB system could induce significant multi-specific T cell responses, leading to decreased serum and hepatic HBV antigen and DNA levels and transient elevation of serum alanine aminotransferase activity.
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