Silent sabotage: How hepatitis B virus-miR-3 disarms innate immunity through cGAS-STING suppression

Abstract

In this editorial, we comment on the article by Xu et al published in the recent issue of the World Journal of Hepatology. The hepatitis B virus (HBV) has evolved sophisticated mechanisms to evade host innate immunity, a hallmark of its persistent infections. This study highlights a pivotal role for HBV-encoded microRNA, specifically HBV-miR-3, in undermining the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING)-IFN signaling axis. This pathway is critical for recognizing viral DNA and subsequent production of type I interferons, key antiviral cytokines. HBV-miR-3 achieves this immune evasion by directly downregulating the expression of cGAS, an essential DNA sensor, and STING, its downstream adaptor. By silencing these components, HBV-miR-3 disrupts the activation of downstream interferon regulatory factor 3 and Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells transcription factors, thereby blunting interferon beta production and antiviral gene expression. This strategy allows HBV to persist in hepatocytes by dampening innate immune responses and contributes to immune tolerance, fostering chronic infection. Understanding the role of HBV-miR-3 provides novel insights into HBV pathogenesis and identifies potential therapeutic targets to restore antiviral immunity. Targeting HBV-miR-3 or reactivating the cGAS-STING-IFN pathway could offer promising strategies to counteract HBV immune evasion and resolve chronic infection.

Key Words: Hepatitis B; MicroRNA; Gene expression; Immunity; Treatment

Core Tip: Hepatitis B virus (HBV) evades innate immunity through HBV-miR-3, which suppresses the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-IFN pathway, a critical antiviral defense mechanism. By downregulating cGAS and STING, HBV prevents interferon production, allowing the virus to persist and promoting chronic infection. Targeting HBV-miR-3 or restoring this immune pathway could offer new therapeutic strategies to enhance antiviral immunity and combat HBV-related diseases.

TO THE EDITOR

Hepatitis B virus (HBV) is an enveloped double-stranded DNA (dsDNA) that remains a formidable global health challenge, with chronic infections affecting millions worldwide. The World Health Organization reported that as of 2022, the prevalence of individuals with chronic HBV infection worldwide was 254 million, with a mortality of approximately 820000[1]. Despite the availability of vaccines and antiviral therapies, HBV persists in hepatocytes through highly evolved immune evasion strategies[2]. Among these, the virus leverages its encoded microRNA, HBV-miR-3, to manipulate key innate immune pathways, ensuring its survival and continued replication. Recent research has highlighted the role of HBV-miR-3 in downregulating the [cyclic GMP-AMP (cGAMP) synthase (cGAS)- stimulator of interferon genes (STING)-IFN] signaling axis, a critical antiviral defense mechanism, which sheds new light on a novel dimension of HBV-mediated immune modulation[3]. As discussed in the recent article by Xu et al[4] in the latest issue of the World Journal of Hepatology, HBV-miR-3 plays a crucial role in modulating host immune responses and providing a glimpse into potential therapeutic targets for HBV infection.

C-GAS-STING pathway in antiviral defense

The presence of uncommon DNA in the cytoplasm, from cellular damage or infection, leads to an immune response[4]. The most robust response is via the cGAS-STING pathway; the dsDNA activates cGAS, which in turn produces cGAMP, which acts as a secondary messenger that binds and activates STING, which is a vital immune regulator[5]. The activated STING recruits TANK-bindings kinase 1, which phosphorylates STING and interferon regulatory factor 3 (IRF3), therefore activating it, which then enters the nucleus and induces the transcription of type 1 interferons[5]. Additionally, STING also recruits IkB kinase, which catalyzes the phosphorylation of Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells transcription factors (NF-kB) inhibitor IkBa[5]. That, in turn, promotes the transcription of target inflammatory cytokines[5].

HBV-miR-3 and its role in immune evasion in chronic HBV infection

The cGAS-STING pathway plays a central role in host antiviral defense by detecting cytosolic viral DNA and triggering the production of IFNs[3]. These IFNs orchestrate a broad antiviral response by activating immune cells and upregulating antiviral genes. However, HBV-miR-3 effectively disrupts this cascade at multiple levels. By targeting cGAS, HBV-miR-3 suppresses the initial sensing of viral DNA, preventing activation of the STING adaptor protein. Without this activation, downstream transcription factors such as IRF3 and NF-kB fail to initiate the antiviral response, reducing IFN-β production[6]. This impairment allows HBV to evade the immune system, allowing HBV replication and establishing chronic infection[6].

As reported by Xu et al[4], suppressing the cGAS-STING-IFN pathway by HBV-miR-3 has significant implications for both viral persistence and disease progression[3]. By dampening innate immune signaling, HBV fosters an environment of immune tolerance within the liver, allowing the virus to evade immune clearance. This evasion not only facilitates chronic infection but also increases the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), all of which are long-term complications of HBV infection.

Clinical implications and therapeutic potential of targeting HBV-miR-3

In one multi-center, randomized phase III clinical trial, the relationship of HBV-miR-3 and HBV replication and the predictive value of HBV-miR-3 was studied who were given PegIFN-alpha treatment[7]. PegIFN-alpha is an anti-viral, anti-proliferative, and immune-regulatory agent[7]. It has been found that HBV-miR-3 is positively correlated with HBV pgRNA, HBV DNA, HBeAg, and HBsAg[7]. Here, HBV-miR-3 was used as a surrogate marker for HBV replication and was found to be closely related[7]. It was also found to have a positive correlation with HBsAg levels[7]. Additionally, it was found that HBV-miR-3 can be used as a predictor of HBeAg seroconversion in patients treated with PegIFN-alpha[7]. However, it should be noted that, there is not a widely available agent for measuring HBV-miR-3[7]. Additionally, this study was performed only in HBeAg-positive patients and not HBeAg-negative, which is a limitation of the study[7]. This study further supports the utility of HBV-miR-3 in preventing long-term complications of chronic HBV infection, and supports the findings presented by Xu et al[4].

In another study, it was found that in HBV-related HCC tissue samples, samples that contained higher expression of HBV-miR-3 had poor overall survival[8]. Additionally, there was a higher correlation between vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Factor Inhibiting Hypoxia-inducible factor -1 (FIH-1) expression[8]. FIH-1 was found to be a tumor suppressor and is a target of many tumor promoters[8]. HBV-miR-3 inhibited FIH-1 expression, leading to the up-regulation of HIF-alpha and VEGF-A, which promoted angiogenesis in HCC[8]. This discovery allows for an additional pathway where HBV-miR-3 inhibition can have therapeutic benefits in HCC[8].

Understanding the intricate role of HBV-miR-3 in immune evasion opens new avenues for therapeutic intervention. Strategies aimed at counteracting HBV-miR-3 function or restoring the cGAS-STING-IFN pathway could reinstate host immune defenses, enhancing viral clearance. Small-molecule activators of STING, cGAS mimetics, or targeted inhibition of HBV-miR-3 could provide new treatment paradigms for chronic HBV infection. Although the work put forth by Xu et al[4] shows excellent strides to help expand treatment modalities for HBV it should be noted that the limitations of their study included, a lack of in vivo experiments, absence of cGAMP and STING agonists or inhibitors, and no pathological tissue evidence. Thus, these are domains that need to be further explored. Nevertheless, combining these novel strategies with existing antiviral therapies may improve treatment outcomes and reduce the burden of HBV-related diseases.

CONCLUSION

In conclusion, HBV-miR-3 is a critical viral tool for suppressing the cGAS-STING-IFN axis to subvert innate immunity. Its ability to silence key antiviral signaling components highlights the virus’s adaptive capacity to persist despite host defenses. Addressing this immune evasion mechanism through targeted therapeutics could pave the way for more effective interventions against chronic HBV infection. As research continues to uncover the molecular intricacies of HBV-host interactions, the insights gained from studies such as the one by Xu et al[4] may ultimately bring us closer to eradicating HBV.