Functional Comparison of Interferon‐α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon‐α and Interferon‐γ Signaling

Abstract

Background and Aims Interferon (IFN)‐α, composed of numerous subtypes, plays a crucial role in immune defense. As the most studied subtype, IFN‐α2 has been used for treating chronic hepatitis B virus (HBV) infection, with advantages of finite treatment duration and sustained virologic response, but its efficacy remains relatively low. This study aimed to screen for IFN‐α subtypes with the highest anti‐HBV potency and to characterize mechanisms of IFN‐α–mediated HBV restriction. Approach and Results Using cell culture–based HBV infection systems and a human‐liver chimeric mouse model, IFN‐α subtype–mediated antiviral response and signaling activation were comprehensively analyzed. IFN‐α14 was identified as the most effective subtype in suppression of HBV covalently closed circular DNA transcription and HBV e antigen/HBV surface antigen production, with median inhibitory concentration values approximately 100‐fold lower than those of the conventional IFN‐α2. IFN‐α14 alone elicited IFN‐α and IFN‐γ signaling crosstalk in a manner similar to the combined use of IFN‐α2 and IFN‐γ, inducing multiple potent antiviral effectors, which synergistically restricted HBV replication. Guanylate binding protein 5, one of the most differentially expressed genes between IFN‐α14–treated and IFN‐α2–treated liver cells, was identified as an HBV restriction factor. A strong IFN‐α–IFN‐α receptor subunit 1 interaction determines the anti‐HBV activity of IFN‐α. The in vivo anti‐HBV activity of IFN‐α14 and treatment‐related transcriptional patterns were further confirmed, and few adverse effects were observed. Conclusions A concerted IFN‐α and IFN‐γ response in liver, which could be efficiently elicited by IFN‐α subtype 14, is associated with potent HBV suppression. These data deepen the understanding of the divergent activities of IFN‐α subtypes and the mechanism underlying the synergism between IFN‐α and IFN‐γ signaling, with implications for improved IFN therapy and HBV curative strategies.

Qualitative Differences Between the IFNα subtypes and IFNβ Influence Chronic Mucosal HIV-1 Pathogenesis

“…One possibility is that these altered IFNβ-specific genes (such as those that decreased protection from DNA damage) may directly contribute to CD4+ T cell death, in line with previous studies linking IFN-Is and CD4+ T cell depletion [91,92]. Given the predicted pleiotropic effects of IFNβ, our data also raise concerns in utilizing IFNβ for treating chronic Hepatitis B virus infections that became refractory to IFNα treatment [76,93,94]. Notably, IFNβ administered <7 days post-symptom onset may help resolve infection with the novel pandemic coronavirus, SARS-CoV-2 [95].…”

“…Our group and others reported diverse antiviral potencies of the IFNα subtypes and IFNβ that correlated with their IFNAR binding properties. These data emphasize the contribution of quantitative differences in IFNAR signaling in controlling acute viral infection [12][13][14][15]76]. However, data from multiple in vivo studies also revealed that the IFNα subtypes may have Expression levels were based on TMM-transformed counts.…”

Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes

“…The PacBio circular consensus sequencing reads analysed in this study have been previously published and can be found in the European Nucleotide Archive (PRJEB12450) [1]. The RNA-seq libraries of hepatitis B virus (HBV)-positive biopsy samples of human liver tumours and tissues, and portal vein tumour thrombosis (129, 182 and 92 libraries, respectively), and HBV-infected primary human hepatocytes (83 libraries) and human cultured cells HepaRG (4 libraries) and HepG2-NTCP (11 libraries) were downloaded from the Sequence Read Archive [2–18] (see the metadata in Table S1, available with the online version of this article).…”

Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

“…High costs and adverse side effects have also limited the use of IFN-α. Alternatives are being investigated and an iterative approach has led to the identification of new IFNs with increased potency, such as the recently described IFN-α 14[ 203 ].…”