Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies

Abstract

Chronic hepatitis B virus (HBV) infection remains a major challenge for clinicians, as there are only two types of approved therapies: interferon-alpha (IFN-α) or its pegylated form, Peg-IFN-α and nucleoside analogs (e.g. tenofovir, entecavir...). The first are used as finite-duration treatments of around 48-52 weeks, while the second must be taken life-long to prevent rebound. Other immune-modulators, including other types of recombinant IFNs and cytokines/chemokines, could be developed for treating chronic hepatitis B. Alternatively, strategies aimed either at restoring or favoring the endogenous production of IFNs, cytokines and/or chemokines, or at alleviating HBV-mediated inhibitory processes could also be envisaged. In this article, we review current investigational, preclinical and clinical efforts to implement immune-modulatory components in the therapy of chronic hepatitis B. This review forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B".

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

“…Current treatments for chronic hepatitis B include type I interferons for a fraction of the patients [11], and the better tolerated nucleos(t)ide analogs (NAs) inhibiting reverse transcription for the majority [12]. Either therapy may achieve control of infection but rarely leads to a cure because cccDNA is not directly targeted; even after recovery from acute self-limited hepatitis B cccDNA is not completely eliminated [13,14].…”

Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts

“…Recently, a large body of evidence has shown that many IFNs/cytokines, including IFN-α, IFN-γ, IFN-β, IFN-λ, IL-6, TNF-α, and IL-1β were capable of inhibiting HBV replication in hepatocytes, in the absence of immune cells [78,79,100,107]. These innate effectors are capable of inhibiting the transcription of cccDNA (thought to be through distinct molecular mechanisms; unpublished data), and some of them are also capable of inducing the degradation of cccDNA in vitro, as initially shown with LT-βR agonists, which were particularly potent in this respect [100].…”

“…If the stimulation of immune cells capable of locally and temporally producing either IFN-α (via pDC), IFNs-λ (via BDCA3 + cells) or IL-1β (via myeloid cells), which have direct anti-HBV properties [107], which is a sound approach theoretically, and could be achieved for instance by PRR agonists, a cell-therapy based on pDC or BDCA3 + DC loaded with HBV-derived peptides could also be an interesting approach. Indeed, these cells could both produce cytokines and elicit T-cell functions via their APC properties.…”

New horizon for radical cure of chronic hepatitis B virus infection

“…HBV has been shown to downregulate TLR2 expression in patients with chronic HBV infection [66] . Thus, innate immunity alteration plays a role, at least in part, in the pathogenesis of chronic HBV infection and TLR7 agonists have been applied as immunemodulatory components [67,68] . On the other hand, the effect of IFNα on intrahepatic cccDNA has been recently explored [69] , and IFNα in addition to lymphotoxinβ receptor (LTβR) activation has been shown to induce cccDNA degradation through upregulation of nuclear APOBEC3 deaminases [70] .…”

“…Other immunotherapeutic approaches to HBV infec tion include administration of cytokines, such as IFNγ, IL6, IL1β, LTβRagonists and/or TLR7 agonist, as well as IFNγ and TNFα which were shown to cause silencing or degradation of cccDNA [67] . This strategy may be more effective in the complete eradication of HBV infection than strategies involving the activation of HBVspecific cells, suggesting that only cytokine administration results in the elimination of cccDNA.…”