# Hijacking JAKis: JAK inhibitors as potential antiviral molecules, a mini review

Claudie Eber, Eloi Verrier

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## To cite this version:

Claudie Eber, Eloi Verrier. Hijacking JAKis: JAK inhibitors as potential antiviral molecules, a mini review. Antiviral Research, 2025, 237, pp.106153. 10.1016/j.antiviral.2025.106153. hal-05081448

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# Hijacking JAKis: JAK inhibitors as potential antiviral molecules, a mini review

Claudie Eber, Eloi R. Verrier*

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University of Strasbourg, Inserm, ITM UMR_S1110, Strasbourg, France

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## ABSTRACT

Janus kinases (JAKs) are key players in the innate immune response and inflammation, catalysing the phosphorylation of STAT proteins, which ultimately leads to the expression of pro-inflammatory and antimicrobial genes. In this context, specific inhibitors of JAK kinases, or JAKis, have been extensively developed, with some already in clinical use for the treatment of chronic inflammatory diseases. However, the interactions between JAK kinases and viral replication appear to be far more complex than initially expected, with some JAKis showing unexpected antiviral properties against different classes of viruses. This mini review summarizes current knowledge about the interactions between JAK proteins and viral infections and discusses the antiviral potential of JAK inhibitors in the development of innovative therapeutic strategies.

## 1. Introduction

Janus kinases (JAKs) are non-receptor tyrosine kinases with key functions in signal transduction, catalysing the phosphorylation of STAT adaptor proteins upon cytokine binding to their receptors. Although the term "Janus" refers to the Roman dual-faced god due to the presence of two phosphate-transferring domains, JAK originally stood for "Just Another Kinase" following its characterization among a panel of other kinases (Wilks, 1989; Agashe et al., 2022). In mammals, four JAKs have been identified that play critical roles in modulating immune responses and inflammation. In the context of viral infections, JAKs are key components of the interferon (IFN)-mediated innate immune response. Given their central role in regulating inflammation and immunity, JAKs have been recognized as promising therapeutic targets for chronic inflammatory diseases, autoimmune disorders, and cancer. Numerous JAK inhibitors (JAKis) have been developed, designed to target the ATP-binding pockets of the tyrosine kinases (Schwartz et al., 2017; Shawky et al., 2022). Although the structural similarities between JAKs complicate the development of highly specific inhibitors, JAKis are generally well-tolerated and safe (Schwartz et al., 2017). JAKis are clinically approved worldwide for treating inflammatory diseases (such as rheumatoid arthritis and atopic dermatitis) and cancers (e.g., myelofibrosis) (see review (Wei and Liu, 2023):). Interestingly, recent studies have revealed an unexpected proviral role of JAKs in viral infections, shedding light on their potential antiviral properties and opening new clinical applications for JAK inhibitors (JAKis). With the

approval of numerous JAKis for clinical use worldwide, opportunities for rapid drug repurposing in this context are emerging. This review summarizes current knowledge on the interactions between viral infections and JAKs and discusses the potential of JAKis in antiviral therapies.

## 2. Janus kinases in infection and immunity

Four Janus kinases have been identified in mammals: JAK1, JAK2, JAK3, and TYK2, which are associated with cytokine receptors and control signal transduction from the cell surface to the nucleus (Fig. 1). All JAKs share the same seven domains, including JH1 (the kinase domain) and JH2 (the pseudo-kinase domain), which plays a key role in regulating kinase activity (reviewed in (Agashe et al., 2022; Shawky et al., 2022). Most JAKis target the ATP-binding pocket of JAKs, impairing their kinase activity (Shawky et al., 2022). The binding of cytokines to their receptors leads to the transphosphorylation and activation of JAKs. Activated JAKs interact with STAT adaptor proteins, ranging from STAT1 to STAT6, including STAT5a and STAT5b (Agashe et al., 2022). JAK-mediated STAT phosphorylation then triggers their translocation to the nucleus, where they act as transcription factors. In the context of viral infection, JAKs play key roles in the innate immune response. Upon recognition of viral motifs by pattern recognition receptors (PRRs), type-I and type-III interferons (IFNs) are expressed and secreted from the infected cells. The autocrine and paracrine binding of IFNs to their specific receptors leads to the phosphorylation of STAT1

This article is part of a special issue entitled: Host-directed approaches published in Antiviral Research.

* Corresponding author.
E-mail address: e.verrier@unistra.fr (E.R. Verrier).
and STAT2 by TYK2 and JAK1, respectively. This JAK/STAT signal
transduction pathway induces the expression of hundreds of
interferon-stimulated genes (ISGs), some of which exhibit antiviral
properties against a wide range of viruses (Schoggins, 2019). Despite
their major role in the antiviral response, several studies have reported
unexpected proviral functions of JAKs, which could be exploited in
antiviral strategies.

3. Targeting retrovirus dependency on the JAK/STAT pathway

Human immunodeficiency virus 1 (HIV-1) infection of immune cells, such as lymphocytes and macrophages, triggers pro-inflammatory and immune responses through the activation of multiple STAT proteins (Bovolenta et al., 1999; Kohler et al., 2003). The activation of these responses is associated with increased viral production and persistence (Gavegnano et al., 2014; Reece et al., 2022), suggesting a proviral role of the JAK/STAT pathway in HIV replication and persistence. In this context, the potential of JAK inhibitors (JAKis) against HIV infection has been thoroughly investigated over the last decade (Ezeonwumelu et al., 2021). Notably, JAKis have been shown to impact the HIV life cycle in a multimodal manner. Initially, it was demonstrated that ruxolitinib, which inhibits JAK1 and JAK2, and tofacitinib, a non-selective JAK inhibitor, can block cellular infection by HIV-1, HIV-2, and other retroviruses in lymphocyte and macrophage models (Gavegnano et al., 2014). Moreover, both drugs inhibit the reactivation of latent HIV-1, supporting the potential of JAKis as potent antiretroviral agents targeting HIV reservoirs (Gavegnano et al., 2017). These effects on replication and latency were further confirmed with baricitinib, another JAK1/2 inhibitor, in HIV-infected CD4⁺ T cells (de Armas et al., 2021). Additionally, a recent study demonstrated that JAKis may affect CCR5 expression on the surface of CD4⁺ T cells, rendering them resistant to HIV infection (Wang et al., 2024). The importance of the JAK/STAT pathway in HIV infection has also been highlighted through high-throughput drug screening, identifying it as a promising cellular druggable target (Yeh et al., 2020). In this study, filgotinib, a JAK1-specific inhibitor, was shown to modulate viral splicing, inhibit viral transcription, and reduce the proliferation of HIV-infected cells,

underscoring the critical role of JAK1 in the HIV life cycle (Yeh et al., 2020). From a clinical perspective, ruxolitinib was recently evaluated in a randomized trial involving HIV patients on antiretroviral therapy, where it demonstrated a reduction in immune activation and HIV persistence markers (Marconi et al., 2022). Interestingly, cerdulatinib, a JAKi under development for the treatment of hematological malignancy, as well as upadacitinib, demonstrated potent anti-T-cell leukemia/lymphoma activity in the context of the infection by another retrovirus, the human T-cell leukemia virus type 1 (HTLV-1), highlighting the complexity of the interaction between viruses infecting the immune cells and JAKis (Ishikawa et al., 2018; Daanthanasanmak et al., 2021). Taken together, these studies underscore the significant potential of JAKis in the context of retrovirus infection, although further research is needed to confirm their efficacy in clinical settings.

4. JAK1 inhibitors in HDV infection

The interaction between hepatitis delta virus (HDV) infection and the innate immune system is complex. HDV is a small, defective virus responsible for the most severe form of chronic viral hepatitis, as it requires co-infection of hepatocytes with hepatitis B virus (HBV), the leading cause of hepatocellular carcinoma worldwide (Turon-Lagot et al., 2020). Although pegylated-IFNα-based therapies were widely used in the past, HDV replication appears to be only weakly susceptible to IFN treatment, and viral cure is rarely achieved. Moreover, HDV induces an endogenous MDA5-mediated IFN response that is largely inefficient in counteracting viral replication (Zhang et al., 2018). Interestingly, JAK1 was identified as a potential proviral factor for HDV replication in a loss-of-function screen for HDV-related cellular factors (Verrier et al., 2020), and the mechanism of action was recently elucidated (Heuschkel et al., 2024). The proviral activity of JAK1 appears to be independent of its role in the innate immune response but relies on JAK1-mediated phosphorylation of ERK1/2. This phosphorylation, in turn, catalyses the phosphorylation of the small delta antigen (HDAg), thereby enhancing HDV replication (Heuschkel et al., 2024) (Fig. 1). In this context, several specific JAK1 inhibitors, including upadacitinib, oclacitinib, and filgotinib, showed potent antiviral activity against HDV,

<figure><img src="image_6.png" /><figcaption>Fig. 1. Interactions between JAKis and virus infections. Created in BioRender. https://BioRender.com/ijvun0s.</figcaption></figure>
in contrast to the JAK2 inhibitor fedratinib (Heuschkel et al., 2024). Preclinical studies in animal models are now required to evaluate the antiviral potential of these inhibitors in vivo. Of note, caution should be exercised regarding the potential reactivation of HBV infection during JAKi treatment, as this may have significant clinical consequences. This issue should be carefully assessed before advancing these inhibitors into clinical trials (see below).

## 5. Interactions between HSV-1 and JAKis

Herpes simplex virus 1 (HSV-1) infections are common viral infections in the human population. The virus can persist in the organism and establish latency, with periodic, usually mild, reactivations triggered by environmental factors (Kotton and Kotton, 2022). In an effort to compare different screening platforms for anti-HSV-1 antivirals, Aiuto et al. observed a potent antiviral effect of the JAK2/3 inhibitor AT9283 in HSV-1-infected neurons, though this effect was less pronounced in Vero cells and neural progenitor cells (D'Aiuto et al., 2017). However, at this stage, there is no clear evidence that the observed antiviral effect is directly correlated to the inhibition of JAK2 or JAK3. It remains unclear whether other mechanisms are involved, as AT9283 is also known to inhibit additional targets, including Aurora kinase A and B (Kimura, 2010). In this context, Krzyzowska et al. recently demonstrated that treatment with tofacitinib was associated with increased HSV-1 infection and worse outcomes in a mouse model (Krzyzowska et al., 2022). This was attributed to the suppression of the virus-induced immune response, suggesting an absence of antiviral effects of specific JAK inhibitors on HSV-1 infection (D'Aiuto et al., 2017).

## 6. Virus reactivation in the context of JAKi treatment

JAKis were initially developed as immunosuppressive molecules for autoimmune and chronic inflammatory diseases. In this context, independently of their direct effects on the viral life cycle, JAKis can be used clinically to improve outcomes in viral pathogenesis involving the immune system, notably in cases of severe inflammation, such as SARS-CoV-2-induced cytokine storms and inflammatory damage (reviewed in (Li et al., 2023)). Notably, baricitinib, a JAK1/2 inhibitor, is the first JAK inhibitor (JAKi) to receive FDA approval for use in a viral disease, specifically for hospitalized COVID-19 patients (Jain et al., 2023). By inhibiting JAK1 and JAK2, baricitinib blocks the induction and release of key inflammatory cytokines, including IL-6 and IL-12, thereby preventing immune dysregulation and cytokine storm (Jain et al., 2023). Moreover, several JAKis with anti-inflammatory effects have been shown to protect mice from influenza A virus-induced inflammation and death (Yu et al., 2024). However, due to their immunosuppressive properties, JAKis have been widely associated with opportunistic viral infections or viral reactivation in the context of latent or chronic infections in patients undergoing treatment for chronic inflammatory diseases (Ezeonwumelu et al., 2021). A recent narrative review concluded that the risk of serious or opportunistic viral infections in patients on JAKi therapy is low but more pronounced compared to the general population (Mansilla-Polo and Morgado-Carrasco, 2024). Additionally, a recent meta-analysis highlighted an increased risk of varicella-zoster virus reactivation in patients receiving JAKi treatment (Ireland et al., 2025). Prior to this, the association between JAKis and Herpesviridae reactivation had been extensively discussed (Sunzini et al., 2020). Opportunistic human cytomegalovirus (HCMV) infections have also been reported in patients treated with tofacitinib (Winthrop et al., 2016). Although a meta-analysis suggested that JAKi use is relatively safe in chronic HBV patients (Hong et al., 2023), a recent study reported a case of HBV reactivation in a patient undergoing upadacitinib treatment for rheumatoid arthritis, leading to fulminant hepatitis that required urgent liver transplantation (Khan et al., 2024). This raises the question of the use of this molecule against the HBV satellite virus HDV in a context of co-infection, although the compound appears to be very

potent in vitro. Similarly, HBV reactivation has also been reported in patients treated with baricitinib (Harigai et al., 2020). Finally, a recent study demonstrated that JAK inhibition is associated with increased replication of hepatitis E virus (HEV), which is known to induce chronic infections in immunosuppressed patients (Kinast et al., 2023). Taken together, these cases highlight the potential interactions between JAKis and increased viral infections or reactivation in patients, as well as the potential limitations of using JAKis against viral infections.

## 7. Conclusions

JAK inhibitors (JAKis) are potent and theatrically safe immunosuppressive agents, even after long-term treatment (Farnos et al., 2024). Of note, more safety data are needed to definitely confirm this statement, as the FDA added a new black box warning on approved JAKis about an "increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions" in 2021, based on a surveillance study (Kragstrup et al., 2022). However, their current safety profiles and approval status by the FDA support the possibility of rapid repurposing, as has been discussed for many dermatological diseases (Sideris et al., 2020), especially for short term treatments. In this context, emerging evidence suggests an unexpected antiviral effect of several JAKis against viruses from different classes (Fig. 1), indicating their potential for use in treating viral infections where therapeutic options are currently limited. Although it may seem paradoxical to propose new therapeutic strategies against viral infections based on immunosuppressive molecules, the risk of viral reactivation must be carefully weighed, especially given the proposed therapeutic windows for their use. Unlike long-term JAKi treatments for chronic inflammatory diseases, a short-term antiviral regimen, if sufficiently effective, could lead to a successful viral cure with a limited risk of opportunistic viral infections and side effects. Of note, in addition to this risk, the inhibitory activity of JAK inhibitors (JAKis) in the immune control of ongoing viral infections must be carefully assessed. Thus, the ability of virus-induced IFN production to limit viral replication must be comprehensively described for each pathogen targeted by JAKis to determine the balance between their pro- and antiviral effects and identify the factors that may influence this balance. This includes the timing and duration of treatment. In this context, it is interesting to note that HDV infection is only weakly affected by the IFN response it induces, as suggested by in vitro studies (Zhang et al., 2018; Lucifora et al., 2023), which may explain the high antiviral potential of JAKis against this virus. Moreover, the proviral effect of JAK1 on HDV replication appears to be independent of the innate immune response but dependent on JAK1's ability to induce ERK1/2 phosphorylation (Heuschkel et al., 2024), thus decoupling both processes. On the other hand, HIV-1 appears to be sensitive to IFN-induced restriction factors (Altfeld and Gale, 2015), highlighting the importance of thoroughly understanding the mechanisms underlying JAK-mediated pro- and antiviral activities in viral infections. In this regard, further research in preclinical models is needed to evaluate the potential of JAKis as clinically viable antiviral agents with minimal risk of side effects, paving the way for the development of new antiviral strategies.

### CRediT authorship contribution statement

Claudie Eber: Writing – original draft, Writing – review & editing.
Eloi R. Verrier: Writing – original draft, Investigation, Funding acquisition.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
## Acknowledgment

This work of the Interdisciplinary Thematic Institute IMCBio+, as part of the ITI 2021–2028 program of the University of Strasbourg, CNRS and Inserm, was supported by IdEx Unistra (ANR-10-IDEX-0002), and by SFRI-STRAT'US project (ANR-20-SFRI-0012) and EUR IMCBio (ANR-17-EURE-0023) under the framework of the French Investments for the Future Program. This work was also supported by the French National Research Agency (ANR, grant number ANR-21-CE15-0035-01 DELTArgel). Fig. 1 was created in BioRender. Verrier, E. (2025) https://BioRender.com/ijvun0s. This manuscript has benefited from language refinement using ChatGPT (OpenAI) to improve readability and clarity.

## Data availability

No data was used for the research described in the article.

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