Background

Diseases caused by virus infections account for millions of lost disability-adjusted life years (DALYs, a measure of disease burden) [1]. Increasing evidence suggests that the environment is an important factor affecting the host's response to virus infections. However, how environmental factors play a role in regulating the host's response to virus infections remains to be explored [2]. As an important environment-sensing ligand-inducible transcription factor, AHR plays a non-negligible role after virus infections. In addition, AHR can affect tumor growth, survival, migration and invasion by participating in cell proliferation, apoptosis and immune metabolism process [3]. In particular, the function of AHR has two sides: under the stimulation of polycyclic aromatic hydrocarbons (PAHs), halogenated aromatic hydrocarbons (HAHs) and other ligands, AHR can promote tumorigenesis and facilitate virus replication in vivo [4]. However, after activation by benzothiazoles, aminoflavone (AF), and other compounds, it can function as a tumor suppressor [5]. The powerful biological function of AHR has attracted researchers to explore it continuously, ho** to use AHR as a breakthrough to provide the basis for the treatment of related diseases. At present, AHR-targeting drugs are mainly AHR agonists, selective AHR modulators (SahRMs) and AHR antagonists, they can alter AHR activity in a ligand-dependent manner and affect the transmission of related signaling pathways [6].

Considering that AHR does not only function as a receptor, it is also a special E3 ubiquitin ligase and a transcription factor located in nucleus after being stimulated, the mechanism of its action is complex and variable [7, 8]. At the same time, the situation of the virus infection is even more changeable. Some are latent infection, while others are rapidly lytic replication. At different stages of virus infection, the products encoded by the virus have intricate effects on the host, and the immune response against the virus is also specific [9]. That is to say, it is still essential for researchers to explore theoretical evidence to support medications which targeting AHR signaling pathways.

Here, we mainly summarize the effects of several different virus infections on the AHR signaling pathways, and the effects of the AHR signaling pathway on virus replication and proliferation in turn. We aim to provide a solid theory for the future search for antiviral drugs targeting AHR.

AHR function

AHR is a kind of basic helix–loop–helix (bHLH) Per–Arnt–Sim (PAS) homology domain protein belonging to the bHLH superfamily of transcription factors [10]. The functional domain of AHR protein consists of three parts: the bHLH domain, PAS domain, and a glutamate-rich domain (Fig. 1). The bHLH domain is located at the N-terminus of the AHR protein and assists AHR binding to the promoter region of target genes and protein dimerization. The PAS domain assists in the formation of protein complexes by linking to the AHR nuclear transporter (ARNT) and binding to ligands. The C-terminal region is a glutamate-rich domain that plays a role in recruitment and transcriptional activation [11]. AHR was first discovered as a hydroxylase "inducer" by Poland and Glover in 1973 by using environmental chemicals as probes [12]. In 1974, mice with different genetic backgrounds were found to show different susceptibility to environmental chemical 2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD), possibly as a result of the polymorphisms in this unidentified hydroxylase activator [13, 14]. With the sequencing of the highly conserved N-terminal sequence of AHR in 1991 [15], and the cloning of the AHR gene in 1992 [16, 17], came a better understanding of the AHR as receptors of carcinogenic environmental ligands. Over time, a variety of environmental chemicals, including PAHs, aromatic amines, and non-ortho-substituted planar polychlorinated biphenyls (e.g., PCB-118, PCB-156, PCB-126), were shown to act largely through the AHR [18]. For example, after being stimulated by these chemical ligands, AHR can be transported from the cytoplasm to the nucleus and bind to another protein, ARNT (Fig. 1), to form a heterodimer. This heterodimer targets downstream target genes, activating the corresponding genes' abnormal expression, such as cytochrome P450 1A1/ cytochrome P450 1B1 (CYP1A1/CYP1B1), ultimately leading to cell toxicity, interference with animal endocrine, immunotoxicity, and even occurrence of cancer [10].

Fig. 1
figure 1

The secondary structure of aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT)

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The activation process of AHR involves changes in various protein modifications, such as phosphorylation, ubiquitination, and SUMOylation, which regulate the protein's localization, activity, and stability [19]. Phosphorylation modification mainly affects the localization of AHR in cells. There are 3 phosphorylation motifs of protein kinase C (PKC) on AHR nuclear localization signal (NLS): S12, T22, and S36. Among them, the phosphorylation of S12 and S36 negatively regulates the nuclear entry of AHR and affects the binding ability of AHR to DNA. Phosphorylation of residues near nuclear export signal (NES) regulates AHR localization in cells. Phosphorylation of S68 in AHR NES by mitogen-activated protein kinases 38 (p38) enables AHR to be transported from the cytoplasm to the nucleus. After AHR enters the nucleus, S36 is phosphorylated again, enhancing the AHR complex's activity and promoting gene transcription [20]. The ubiquitination mainly mediates the degradation of AHR after activation, thus playing a regulatory role. The ubiquitination site of AHR is located in the transactivation domain (TAD). Degradation by ubiquitination partially depends on forming the AHR/ARNT heterodimer and binding to DNA [21]. Besides, as mentioned above, AHR can also act as an E3 ubiquitin ligase to promote the ubiquitination and degradation of some sex hormone receptors. SUMOylation enhances AHR stability through inhibition of its ubiquitination. However, this may suppress its transcriptional activity [60]. After HCV infection, host cell metabolism is altered, producing specialized membrane structures and altering organelles, such as double-membrane vesicles and enlarged lipid droplets (LDs), which enable virus replication and assembly [61]. However, the molecular mechanisms of HCV-host interaction are largely unknown. Recently, some researchers found that HCV infection can activate the AHR signaling pathway and upregulate the AHR downstream target gene CYP1A1, promoting the production of LDs. Subsequently, the accumulated LDs can promote the efficient production of progeny viruses [62].

We hypothesize that AHR can regulate the production of triglycerides and LDs, which to some extent determine the replication ability of HCV in host cells. It has also been demonstrated that the transcriptional activity of AHR is elevated in HCV-infected cells, and the level of the AHR endogenous ligand Kyn is also elevated in HCV-infected patients [63]. In addition, lipid accumulation in the liver may also be the basis for the development of HCC, and the lipid accumulation caused by the AHR-CYP1A1 pathway may be closely related to the development of HCC [64].

As early as 2016, Canavese et al. proposed a hypothesis based on the current experimental progress and evidence: After HCV infection, cells promote HCC by regulating the TDO-Kyn-AHR signaling pathway, leading to tumorigenesis. They believe that changes in the expression of AHR pathway-specific genes are associated with the progression of HCV infection and HCC. Interestingly, some researchers recently found that aflatoxin B1 (AFB1), closely related to HCC, can play a role similar to AHR ligand, promote AHR nuclear translocation, and activate the AHR signaling pathway [65].

Human immunodeficiency virus type-1 (HIV-1)

Human immunodeficiency virus type-1 (HIV-1) is an important infectious agent that is responsible for acquired immunodeficiency syndrome (AIDS) [66]. As a kind of successful retrovirus, HIV-1 remains a global health problem of unprecedented dimensions [67]. More than a decade ago, researchers found that AHR activation stimulated by ligand of TCDD or by TCDD chemical homologue 3-methylcholanthrene 3-MC was shown to reactivate HIV-1 from latency [68, 69]. In recent years, through further exploration, researchers demonstrated that AHR was activated by Trp metabolites to promote HIV-1 infection and reactivation [70]. Mechanically, they confirmed that AHR directly binds to the HIV-1 5′ long terminal repeat (5′-LTR) at the molecular level to activate viral transcription and infection, and AHR activation by Trp metabolites increases its nuclear translocation and association with the HIV 5′-LTR. Moreover, they also found AHR could bind to HIV-1 Tat to facilitate the recruitment of positive transcription factors to viral promoters. These findings all suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.

Another researchers elucidated that the activation of AHR could not always facilitate HIV-1 replication. Tonya et al. showed that AHR activation in macrophages caused a block to HIV-1 replication [71]. To be specific, the activation of AHR downregulates the transcription of cyclin-dependent kinase CDK1, CDK2 and associated cyclins, resulting in dNTP depletion and antiviral effects. Totally, the effect of AHR activation on HIV-1 may be disparate in different cell types. It is still essential for us to further elucidate the effect of AHR signaling pathways on HIV-1 latent state and replication.

Epstein–Barr virus

Epstein–Barr virus (EBV) was the first definitive human tumor virus as a member of the human gamma-herpesvirus subfamily. EBV is generally latently infected in host cells and encodes corresponding viral products, such as viral proteins and microRNAs. Studies have found that these viral encoded products may affect the AHR signaling pathway, thereby affecting the occurrence and development of tumors. Here we mainly introduce the effects of three EBV-encoded protein products on the AHR pathway.

EBNA3 facilitates the role of the AHR pathway by promoting AHR nuclear translocation in B lymphocytes

EBV nuclear antigen 3 (EBNA3) is one of the EBV-encoded nuclear antigens indispensable for immunoblastic transformation and sustains the proliferation of B lymphocytes [72]. When EBV infects and maintains latency in B lymphocytes, its encoded viral product protein EBNA3 can interact with XAP2 and AHR. They influence the localization of each other in cells. When exogenous ligands, such as TCDD, interact with the AHR complex, the cytoplasmic localization of AHR affected by XAP2 is counteracted by EBNA3, resulting in nuclear translocation of AHR, which enhances the AHR signaling pathway. It has now been demonstrated that the stability of EBNA3 interaction with AHR is determined by the activation state and the presence of XAP2. Meanwhile, the interaction of EBNA3 with Hsp90 is mediated through XAP2 [73]. It is noteworthy that the nuclear translocation effect of EBNA3 on the AHR is only functional when TCDD acts as a ligand. Without TCDD, the cytoplasmic localization of AHR by XAP2 would be dominant and stronger than the nuclear translocation of AHR by EBNA3. Under this circumstance, EBNA3 cannot promote the nuclear translocation of AHR.

The facilitation effect of EBNA3 on the AHR signaling pathway activated by TCDD was confirmed by Elena V. Kashuba et al. in 2005 [73]. Following this, it was found that the AHR signaling pathway promoted by EBNA3 was associated with EBV reactivation. It has been demonstrated that the AHR complex and EBNA 3 reactivate EBV's immediate-early viral transactivator, BZLF1 [74]. This initiating factor of lytic replication counteracts latent viral signals to a certain extent by blocking the NF-κB signaling pathway (Fig. 4) [75].

Fig. 4
figure 4

Effects of Epstein-Barr virus-encoded products on AHR signaling pathway in B cells. Distinct endogenous and exogenous AHR ligands regulate the metabolism of B cells. EBV-encoded protein EBNA3 enhances dioxin-induced AHR transcriptional activity, which induces the expression of BZLF1. BZLF1 promotes the virus to enter a lytic replication state, inhibits the NF-κB signaling pathway, and affects the expression of PD-L1. EBV-encoded LMP1 can affect the AHR signaling pathway by activating NF-κB

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The expression of AHR in T cells is also induced by the cytokine IL-27. In these cells, AHR interacts with c-Maf, a transcription factor identified in a subset of Tregs [74, 75]. These CD4+ CD25+ Foxp3− c-Maf+ Treg cells, termed Treg-of-B cells, are formed in response to repeated interactions with B cells [76]. Treg-of-B cells express PD-1 and additional checkpoints in regulating Th2, Th1, and Th17 responses under physiological cues that have yet to be fully elucidated (Fig. 5).

Fig. 5
figure 5

Effects of Epstein-Barr virus-encoded products on AHR signaling pathway in Treg cells. EBV-induced production of IL-27 enhances AHR expression, promoting transcriptional activity of c-Maf and Foxp3. There is also an interaction between the AHR signaling pathway and the NF-κB signaling pathway

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LMP1 affects AHR signaling pathway by activating NF-κB in B lymphocytes

EBV is an established factor in systemic lupus erythematosus (SLE) and PD-1 immunobiology [77]. The role of the PD-1 receptor and its ligands in the disease progression of SLE has been identified. In recent years, it has been found that EBV-encoded products can regulate the expression of PD-1 and 2 by affecting the AHR signaling pathway and other pathways that interact with them, such as NF-κB and/or STAT1, thereby affecting the development of SLE (Fig. 5) [78]. The EBV-encoded product latent membrane protein 1 (LMP1) can induce the activation of NF-κB and produce various cytokines in B cells, such as IL-27 subunit, EBI3, BAFF, APRIL, IFN-α, IFN-γ [79, 80]. The newly generated IFN subsequently induces STAT1 activity [81], and these signals, as mentioned earlier, may ultimately play a role in inducing PD-L1 expression in EBV latently infected cells [82]. If more PD-L1 is expressed on B cells, then more PD-1 is attached to it on Th cells, suggesting more severe SLE [83, 84]. Since LMP1 activates the NF-κB pathway to some extent, and there is an interaction between the NF-κB pathway and the AHR signaling pathway[85], we speculate that LMP1 may indirectly affect the AHR signaling pathway by regulating the NF-κB pathway.

LMP2A suppresses the role of the AHR signaling pathway through the ERK signaling pathway in EBV-associated gastric cancer

It was reported that AHR was highly expressed in many types of human malignant tumor tissues and cell lines and was involved in the occurrence of tumors [86, 87]. Medical-related statistics have proved that compared with precancerous lesions, the expression of AHR in gastric cancer (GC) tissue is significantly increased [88]. Latent membrane protein 2A (LMP2A) is one of the EBV-encoded products and is expressed in more than 50% of EBV-infected GC cases [89]. LMP2A not only plays a key role in maintaining the latent state of the virus but also participates in the regulation of various intracellular signaling pathways, such as MAPK/ERK, phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and NF-κB pathway, and is an important molecule in the carcinogenic process [90]. Studies have shown that LMP2A regulates the expression of certain genes by modulating these pathways, affecting tumor progression [91, 92]. Therefore, in recent years, researchers have studied the activation of the AHR pathway in EBV-associated gastric cancer (EBVaGC) and EBV-negative gastric cancer (EBVnGC) cell lines to observe the effect of EBV infection on the AHR pathway in GC cells [93].

Early exploration has proved that LMP2A can activate the MAPK/ERK pathway and promote the accumulation of p-ERK in gastric cancer cells. It also provided direct evidence that the inhibition of AHR expression by LMP2A may be achieved by activating the ERK pathway[93]. There are still many controversies about the role of AHR in tumors. With further study, the researchers found that EBV-infected cells were less sensitive to AHR agonists than EBVnGC cells [92]. Although it limited the progression of cancer on the one hand, which may be related to EBVaGC low lymphatic metastasis and good prognosis, it may also increase the difficulty of treatment with AHR as the target on the other hand. Furthermore, the finding that LMP2A suppresses the role of the AHR pathway through the ERK signal pathway in EBVaGC may provide an important direction for the future treatment of EBVaGC, and we still need more exploration about the effects of EBV infection on AHR signaling pathway.

Human cytomegalovirus (HCMV)

HCMV is a beta-herpesvirus that establishes lifelong asymptomatic infection in most people and is one of the leading causes of congenital disability [94, 95]. After the virus infects cells, it manipulates various aspects of the metabolism to facilitate its replication and spread [96, 97].

Previous studies have found that ectopic expression of the HCMV IE1 protein induces the accumulation of IDO1 RNA levels [98] and reduces the accumulation of kynureninase RNA in fibroblasts [99], which is the enzyme that synthesizes Kyn and catabolizes Kyn, respectively. Therefore, IE1 can enhance the level of Kyn by promoting the synthesis of Kyn and/or reducing the consumption of Kyn. In recent years, some scholars have verified that HCMV infection can activate AHR by upregulating Kyn and activating AHR requires viral gene expression. At the same time, AHR contributes to the efficient production of HCMV progeny. After AHR is activated, it can broadly affect the transcriptome of infected cells. In addition, the authors also found that AHR can promote HCMV-induced G1/S block to cell cycle progression, thereby preventing cell proliferation and preserving metabolic resources for viral progeny [100].

Paradoxically, another research team observed that the expression of hypoxia-inducible factor 1α (HIF1α) was increased after HCMV infection. While exploring the role of HIF in HCMV replication, they found that HIF1α inhibited the concentration of intracellular and extracellular Kyn and the expression of IDO1. HIF1α inhibits AHR activation by regulating the synthesis of the AHR endogenous ligand Kyn, thereby limiting virus replication [101].

The regulation of the AHR signaling pathway after HCMV infection is complex and variable, and it is difficult to clarify its specific and fixed regulatory mechanism, but we can conclude that HCMV infection can indeed exert various effects by affecting the AHR signaling pathway, whether it could prevent cell proliferation or inhibit virus replication.

Other viruses

The effects of other virus infections on the AHR signaling pathway have also been reported. During primary influenza A virus (IAV) infection, the AHR signaling pathway is activated in immune cells, which in turn inhibits dendritic cells (DC) function and initiates the ability of naive CD8+ T cells to diminish host responses and thereby reduce cytotoxic T lymphocytes production. And the authors identified that AHR activation reduced CD209a expression in DC and CCL17 production in the lung and mediastinal lymph nodes (MLN) during IAV infection [102]. It is well acknowledged that human T-cell leukemia virus type 1 (HTLV-1) establishes latent infection in vivo and can be reactivated under certain circumstances [103]. It has been reported in another article that AHR can play its role as a tunable knob that controls HTLV-1 latency-reactivation switching [104]. Specifically, activated AHR binds to HTLV-1 LTR and drives HTLV-1 plus-strand transcription. It has been demonstrated that HTLV-1 latency-reactivation-latency switching in MT-1 cells can be manipulated by adding and removing additional AHR ligands, suggesting that AHR is a potential target for prophylaxis and treatment of HTLV-1-related diseases.

Conclusions

In general, our review discusses the relationship between virus infections and AHR pathways, providing an important direction for the future treatment of virus-associated diseases. The activation of the AHR pathway is significantly related to cell proliferation and migration, which also provides the possibility for AHR as a drug target for disease treatment. It is not difficult to see from the above that AHR activation is a common strategy for most viruses to evade anti-virus immunity and promote virus replication. Although the underlying mechanisms by which viruses activate or inhibit AHR vary, their roles are clear: either to evade the host immune responses or promote self-replication and survival. Exploring the impact of different virus infections on the AHR pathway will help us understand the pathogenic mechanism of viruses regulating AHR and provide more precise, efficient, and potential therapeutic targets for antiviral therapy points.