Like other retroviruses, the integrated HTLV-1 proviral genome is made up of two long terminal repeat sequences, flanking structural genes gag, pol, and env. HTLV-1 also has a unique 1.6 kb accessory region, termed the pX region, which encodes a few regulatory viral proteins when cells are productively infected (14, 20, 21). These mainly include the expression of the trans-activator protein Tax, which is known to hijack multiple intracellular signaling pathways that contribute to inflammation and immune activation, thereby ultimately promoting the proliferation of HTLV-1-infected T-cells and viral dissemination (22, 23). Among those, the nuclear transcription factor NF-κB plays a central role in coordinating various cellular signals that serve as pivotal mediators of inflammatory responses in the form of multiple encoding cytokines and chemokines (IL-1β, IL-2, IL-6, IL-8, TNF-α, MIP-1α/β and RANTES among others) (22, 24–26). The prototypical NF-κB complex corresponds to a heterodimer of the NF-κB1 (p50) and RelA (p65) members of the NF-κB/Rel family of transcription factors (27). Evidence shows that HTLV-1 Tax has developed multiple hijacking strategies to activate NF-κB signaling pathway; First, it induces the phosphorylation and degradation of both IκBα and IκBβ through the activation of the IκB kinase (IKK) complex, resulting in the nuclear translocation of active NF-κB (27–29). Tax also recruits the co-activator protein p300/CBP (30, 31) whose nuclear interaction with the RelA subunit of NF-κB is vital for RelA-dependent gene transcription (32). Finally, Tax stimulates the catalytic activity of the IKK-activating kinase TAK1 and mediates the physical recruitment of IKK to TAK1

in productively infected cells, including Tax-positive HTLV-1-transformed T-cells (33–35). Evidence shows that HTLV-1 Tax induces the secretion of multiple pro-inflammatory cytokines (IL-2, IL-12, TNF-α/β, and IFN- γ) and chemokines (MCP-1, MIP-1α/β, and MCP-3) in immature monocyte-derived dendritic cells (MDDCs) in a NF-κB-dependent manner (36, 37). Jurkat CD4 T-cell line, when treated with Tax, induces transactivation of the MCP1 gene (38). Both peripheral monocyte-derived macrophages (MDMs) and microglia (specialized cells, acting as the brain’s resident macrophages), when cultivated in vitro with HTLV-1 Tax, secrete high amounts of pro-inflammatory IL-1β, and IL-6, and TNF-α cytokines (39). Similarly, HTLV-1 Tax mediates MIP-1α/β and RANTES expression in peripheral mononuclear cells (PBMCs) via the NF-κB signaling pathway (40, 41). Finally, although Tax expression in HTLV-1-infected individuals is tightly regulated and often silenced to evade immune detection, especially in ATLL patients, it can still be reactivated by multiple stressors, such as hypoxia, T-cell reactivation and oxidative stress, thereby sustaining viral persistence and long-lasting proinflammatory immune responses (42–44). So far, HTLV-1 Tax is one of the key viral proteins which has comprehensive executive function associated with developing HAM-TSP and ATLL conditions, that especially contribute in tissue inflammation/damage and T-cell hyperimmune activation (24, 45–48).

Innate immune-mediated inflammation plays a critical role in inhibiting pathogenic viruses through the recognition of multiple viral components by the host pattern recognition receptors (PRRs) (49). In the context of HTLV-1 infection, the replication cycle yields multiple pathogen-associated molecular patterns such as viral RNA, RNA/DNA intermediates, and single- or double-stranded DNA, which are recognized by cytosolic sensors including cGAS, IFI-16, along with Ku70, which activate the STING-TBK-1 axis to induce IRF3-driven type I interferon responses. Endosomal PRRs such as toll-like receptor 3 (TLR3), TLR7/8, and TLR9 also respond to viral RNA or CpG-rich DNA via TRIF- or MyD88-dependent pathways, converging on both IRF3 and NF-κB inflammatory signaling (50). Surface TLRs such as TLR2 and TLR4 actively participate in sensing; For example, the accessory protein HTLV-1 p30 antagonizes TLR4 signaling in monocytes and dendritic cells, thereby deregulating MCP-1, TNF-α, IL-8 and IL-10 production (51). Its regulatory protein Tax robustly activates NF-κB and AP-1 transcription factors, driving expression of IL-2, IL-6, TNF-α, CCL2/MCP-1, and CXCL10 (47, 52), whereas HTLV-1 HBZ protein attenuates IRF3-mediated interferon signaling, dampening IFN-I responses (53). Additionally, HTLV-1 p12 and p8 proteins can both modulate IL-2 receptor signaling and enhance STAT5 activation even in the absence of IL-2, while facilitating immune evasion and cell-to-cell transmission (54, 55). Collectively, this complex interplay of innate sensing and viral countermeasures orchestrates a potent inflammatory and chemotactic cytokine milieu -comprising IL-1β, IL-2, IL-6, TNF-α, CCL2, CXCL10, and RANTES - that underlies chronic inflammation in HTLV-1–associated diseases such as ATLL and HAM-TSP (16, 50). Although there are intricate strategies employed by HTLV-1 to subvert the host innate IFN-I responses that contribute both to viral immune evasion and the development of HTLV-1-associated diseases (50), chronic HTLV-1 infection is still associated with unrelenting host innate sensing and immune activation accompanied by high levels of pro-inflammatory cytokines/chemokines (56–59). This outcome likely results from the host’s continuous, albeit unsuccessful, attempts to eradicate viral infection and maintain tissue homeostasis. In this context, the pro-inflammatory TNF-α cytokine, known for triggering upstream signaling events leading to the autocrine activation of NF-κB pathway (60), is likely one of the critical players of sustained HTLV-1-driven inflammation. Recent studies have shown that anti-TNF-α agents can be effective in treating inflammatory diseases related to HTLV-1 (such as arthropathy, uveitis, and other rheumatic conditions associated with the given viral infection) (61–64). In fact, the inflammatory response triggered by the increased of TNF-α along with IFN-γ and IL-2, mainly by the CD4 T-cell response, is what maintains the chronic inflammatory process in HAM-TSP patients (65–67).

HTLV-1-associated myelopathy/tropical spastic paraparesis is a progressive disease of the CNS that causes weakness or paralysis of the legs, lower back pain, and urinary symptoms, which occur in approximately 2%–3% of HTLV-1 carriers (72). This HTLV-1-related disease is characterized by a hyper-stimulated immune response, which includes elevated levels of inflammatory cytokines and chemokines, and the recruitment/oligonal expansion of virus-specific cytotoxic CD8 T-cells in the CNS; all of which contributes to nerve tissue damage and loss of motor functions in patients. In this context, data show that the sera/plasma and cerebrospinal fluid (CSF) from HAM-TSP patients always display higher protein levels of IL-2, IL-6, IL-17, TNF-α, IFN-γ, MCP-1, RANTES, CXCL9, CXCL10, and CXCL11 when compared to ACs (58, 73–80). Data also show increased ex vivo levels of CSF neopterin in HAM-TSP patients (77, 79–81), which is a molecule synthesized by macrophages upon stimulation with IFN-γ and is indicative of a pro-inflammatory immune status (82). In fact, CSF CXCL9, CXCL10, and neopterin are described as trustworthy prognostic biomarkers for HAM-TSP disease progression (77–79, 81, 83). Although no differences are detected between HAM-TSP patients and ACs, levels of MCP-1 and IL-8 chemokines are higher in the sera and CSF from HTLV-1-infected individuals when compared to HCs (79). Research studies have further confirmed the higher cellular ability of HAM-TSP patients to secrete pro-inflammatory cytokines and chemokines in culture. For example, peripheral blood mononuclear cells (PBMCs) and CD8 T-cells of HAM-TSP patients stimulated or not with Tax peptides display higher mRNA and protein levels of IFN-γ when compared to both ACs and HCs (84–86). PBMCs from HAM-TSP patients further show an increased proportion of IL-17-expressing CD4 T-cells (86) and of inflammatory CD4⁺CD8⁺ T-cell populations whose IFN-γ, TNF-α, IL-17, and CXCL10 productions are one of the most pronounced among stimulated T-cells (87). Immature MDMs from HAM-TSP patients, when incubated in unstimulated cultures, show higher spontaneous secretion of RANTES and CXCL9 chemokines in comparison to both ACs and HCs (88). It is worth noting that pro-inflammatory CD16⁺ monocytes of HAM-TSP patients, whose proportions are increased in PBMCs in comparison to both ACs and HCs (88), are unable to fully mature into dendritic cells and maintain a high production of TNF-α and IL-1β cytokines (89, 90). Similarly, higher proportions of pro-inflammatory monocytes producing IL-12 and MIP-1α, plasmacytoid DCs producing IL-12 and CD56^highCD16^– natural killer cells producing IFN-γ are detected in HAM-TSP blood samples in response to innate immune sensing when compared to ACs (91). The comparative gene expression profiles of polynuclear neutrophils between ACs and HAM-TSP patients have revealed higher expression of multiple genes related to the Nf-kB signaling pathway and pro-inflammatory responses including TNFA, IL6, and IL17 (92). Altogether, this evidence infers that, during HAM-TSP development model, HTLV-1-infected cells in the CNS may produce large amounts of IFN-γ that can induce resident macrophages, DCs, neutrophils and astrocytes to secrete MCP-1, MIP-1α/β, RANTES, CXCL9, and CXCL10 chemokines among others (7, 93–95). The latter recruit more infected cells, including Tax-expressing CD4 T-cells, to the aera along with cytotoxic CD8 T-cells, which constitute a T-helper type 1 (Th1)-centric feedback loop (IL-1β, IL-2, TNF-α, IL-12 and IFN-γ) that results in chronic inflammation in the CNS (95–97).

In addition to the HAM-TSP disease, HTLV-1 infection can cause inflammation in other tissues than CNS. In this context, HTLV-1-infected CD4 T-cells collected from patients suffering from uveitis, which is the second-most frequent HTLV-1-associated disease in Japan after HAM-TSP, also produce large amounts of various inflammatory cytokines such as IL-1, IL-6, TNF-α, and IFN-γ (98, 99). Similarly, evidence shows that the bronchoalveolar fluids (BALFs) from HTLV-1-infected patients with CFA, a chronic inflammatory lung disease of unknown etiology, display elevated levels of MIP-1α and CXCL10 chemokines, which correlate with higher tissue infiltration of activated T-cells (100, 101). Altogether, this indicates that, similarly to HAM-TSP, HTLV-1 infection may contribute to other HTLV-1-associated inflammatory diseases via the chemokine-dependent recruitment of activated T-cells in the eyes (uveitis) and lungs (CFA), thus resulting in chronic tissue inflammation by the sustained release of Th1 pro-inflammatory cytokines.

Adult T-cell leukemia/lymphoma is a highly aggressive mature CD4⁺CD25⁺FoxP3⁺ T-cell neoplasm associated with chronic HTLV-1 infection, which affects around 10 million people worldwide. Although it is obvious that HTLV-1-associated inflammatory conditions (HAM-TSP, uveitis, and CFA) are associated with elevated pro-inflammatory innate and T-cell immune responses, ATLL patients exhibit a rather immunosuppressive profile that is mainly highlighted by the abnormally high production of IL-10 cytokine (102). However, ATLL is a complex and multistep disease, which involves HTLV-1 Tax and HBZ proteins and starts with high proliferation and survival of HTLV-1-infected CD4 T-cells (21, 103). In fact, one of the major hallmarks of HTLV-1-infected CD4 T-cells in ATLL is their ability to proliferate independently of T-cell receptor stimulation, contributing to the immortalization of these infected cells overtime (6, 21, 69). Although survival of HTLV-1-infected ATLL CD4 T-cells mainly depend on IL-10 production (74, 102, 104), evidence shows that the maintenance of elevated proliferation rates is rather supported by their dependency on pro-inflammatory cytokines such as IL-2 and IL-6. In this context, in vitro data confirm that HTLV-1-infected T-cells are dependent on IL-2 for their proliferation, until they get their immortalized status after several weeks in culture (105). Levels of IL-6 in sera are higher in ATLL patients when compared to both ACs and HCs (106, 107). Interestingly, IL-6 levels in ATLL do not only correlate with T-cell proliferation but also with ATLL severity and shorter survival rate in patients (107). Recent comparative transcriptomic analyses of PBMCs between ATLL patients and HCs have revealed that ATLL pathogenesis is associated with the upregulation of many genes related to inflammatory responses such as NFKB1, RELA, IL2, IL17, and TNFA (56, 108, 109). Pro-inflammatory chemokines are also involved in ATLL pathogenesis as they recruit cancer cells into the lymph nodes, spleen, liver, skin and gastrointestinal tract, thereby contributing to cancer spreading in infected patients (63, 69). In fact, constitutive expression of various pro-inflammatory chemokines in HTLV-1-positive ATLL cells, including MCP-1, MIP-1α/β, RANTES, IL-8 and CXCL10, have been reported and involves the HTLV-1 Tax and Nf-κB signaling pathway in the process (38, 110, 111). Higher plasma levels of TNF-α and IL-6 cytokines, and CXCL10 are found in patients with aggressive ATLL when compared to those with indolent ATLL (aka. stable and slow growing form of lymphoma/leukemia usually associated with lesser fever and lesser symptoms), indicating a worsening role of strong inflammatory responses in ATLL disease severity (74, 107). Finally, Tax- and HBZ-transgenic mice, which develop HTLV-1-like impairments such as T-cell lymphoma and systemic inflammation, display higher production of TNF-α and IFN-γ in FoxP3⁺ splenocytes, and of IL-1α/β and IL-6 in ATLL-like cells (112–114).