Interferon dynamics in deltaretroviruses: why HTLV-1 evades, but BLV responds.

Introduction
Human T-cell leukemia virus type 1 (HTLV-1) is a deltaretrovirus that infects tens of millions of people globally [1]. It is the causal agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory condition HAM/TSP or HTLV-1 associated myelopathy/ tropical spastic paraparesis [2–4]. HTLV-1 primarily targets CD4⁺ T-cells, spreads predominantly via cell-cell contact, and often evades detection in plasma, establishing persistent infection with significant oncogenic and neurological sequelae [5, 6]. The lack of effective curative treatments for HTLV-1 infection renders understanding its pathogenesis, particularly the host immune response, crucial for advancing therapy and disease management [7].
Bovine leukemia virus (BLV), another deltaretrovirus closely related to HTLV-1, infects cattle worldwide and is possibly associated with enzootic bovine leukosis, a disease characterized by persistent lymphocytosis and B-cell leukemia or lymphoma in a subset of infected animals [8]. BLV infection is of primary economic concern to the cattle industry due to productivity loss, culling, and trade restrictions [9, 10]. Notably, an increasing body of evidence has suggested that BLV DNA sequences have been detected in human breast tissue, with some studies proposing a potential zoonotic link between BLV infection and breast cancer development in women [8, 11–13]. While the strength and causality of this association remain debated, the possibility underscores the broader public health importance of BLV beyond veterinary medicine. Controlling BLV infection is therefore not only a priority for animal health and food security, but may also help reduce potential zoonotic risks [8, 11–14]. This dual relevance underscores the need for comparative studies on deltaretroviruses to enhance our understanding of their biology and inform strategies for prevention and treatment in both animals and humans, particularly through immune therapy.
The interferon (IFN) family, encompassing type I IFNs (IFN-α/β) and type II IFN (IFN-γ), orchestrates the innate antiviral response, activating signaling cascades such as JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription signaling pathway) and ISGF3 (Interferon-Stimulated Gene Factor 3) that drive expression of interferon-stimulated genes with antiviral functions [15, 16]. However, in HTLV-1 infection, IFN responses may be dysregulated. HTLV-1-encoded proteins (e.g., Tax) induce Suppressor of Cytokine Signaling 1 (SOCS1), which suppresses type I IFN signaling both by inhibiting IRF3 and by impairing downstream JAK-STAT activation [17].
Despite these insights, significant knowledge gaps remain. Why HTLV-1 displays relative resistance to IFN-mediated control while BLV demonstrates greater susceptibility is not fully understood. The contribution of individual IFN subtypes, the induction of specific ISGs, and the interplay with viral immune evasion mechanisms remain incompletely defined. Furthermore, although IFN-based therapies have been clinically trialed for HTLV-1-associated diseases, their effectiveness is limited, and combination strategies with other agents are still under investigation [7]. Meanwhile, BLV remains widespread in global cattle populations, and there is no licensed vaccine or effective antiviral therapy, leaving control dependent on culling or herd management, which is often economically challenging [18].
Critical questions persist regarding how specific IFN subtypes influence viral replication, immune activation, and disease progression across deltaretrovirus models. Dissecting these pathways could clarify why HTLV-1 resists complete IFN-mediated control, whereas BLV is more susceptible to IFN-γ. Additionally, the potential for leveraging ISGs in therapeutic strategies remains underexplored.
This review aims to provide a comprehensive overview of the role of interferons in deltaretrovirus infection, with a focus on both HTLV-1 and BLV, and to explore how differences in viral-host interactions shape the outcome of IFN-mediated responses. In particular, it will highlight recent evidence on the possible zoonotic risk of BLV in relation to breast cancer, emphasizing the importance of controlling infection in both human and animal hosts. Ultimately, the review will evaluate current and emerging therapeutic approaches targeting the interferon axis, discuss their limitations, and propose future directions for harnessing IFN pathways to develop more effective antiviral strategies against deltaretroviruses.

Biological properties and classification of interferons
Interferons are a large group of cytokines that play a pivotal role in regulating innate and adaptive immune responses, particularly in defense against viral infections and in modulating tumor surveillance [19]. They are secreted glycoproteins that act in an autocrine and paracrine manner, primarily through binding to specific cell surface receptors and activating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway [20] (Fig. 1). This activation leads to the transcription of numerous interferon-stimulated genes (ISGs), which orchestrate a wide range of antiviral, antiproliferative, and immunomodulatory activities [21, 22].
The IFN family is broadly classified into three major types: Type I, Type II, and Type III interferons, each differing in gene organization, receptor usage, and biological functions (Fig. 1) [23, 24].

Type I Interferons include multiple subtypes, such as IFN-α, IFN-β, IFN-ε, IFN-κ, IFN-ω, IFN-δ, and IFN-τ [23]. Among these, IFN-α is the most diverse, consisting of multiple isoforms, and is primarily produced by plasmacytoid dendritic cells [25]. IFN-β is secreted by fibroblasts and many other cell types following viral infection and is often the first IFN induced during an antiviral response [24]. IFN-ε, IFN-κ, and IFN-ω are expressed in tissue-specific manners and contribute to mucosal immunity and host defense. In domestic animals, additional type I IFNs are described, such as IFN-δ in pigs and IFN-τ in ruminants; the latter is uniquely expressed by trophoblast cells during early pregnancy, where it plays a crucial role in maternal recognition of pregnancy in cattle and sheep [25, 26]. Despite these functional specializations, type I IFNs act through a common receptor complex composed of IFNαR1 and IFNαR2 subunits and trigger broad antiviral and antiproliferative effects [22, 26]. Advances further highlight the central role of interferon signaling pathways in host defense and disease outcome. Casanova et al. (2024) emphasize that interferon-γ (IFN-γ) is indispensable for immunity against intracellular pathogens, coordinating macrophage activation, antigen presentation, and T-cell–mediated cytotoxicity, while inherited or acquired defects in IFN-γ signaling markedly increase susceptibility to severe infectious diseases [27]. Complementing this concept, studies on type I interferon receptors demonstrate that host genetic variation critically shapes antiviral responses. A systematic review by López-Bielma et al. (2023) identified single-nucleotide variants (SNVs) in IFNαR1 and IFNαR2 that modulate the magnitude and quality of the type I IFN response to SARS-CoV-2 infection, influencing viral clearance and inflammatory balance [28]. Consistently, Yaugel-Novoa et al. (2023) reported a significant association between IFNαR1/IFNαR2 polymorphisms and COVID-19 severity, supporting the notion that impaired receptor signaling can compromise early antiviral defense and predispose individuals to severe disease [29].
Type II Interferon is represented solely by IFN-γ, a cytokine primarily produced by activated T lymphocytes and natural killer (NK) cells [24]. Unlike type I IFNs, IFN-γ signals through a distinct receptor complex, IFNγR1 and IFNγR2, and its functions are more immunoregulatory than directly antiviral [24]. It promotes macrophage activation, enhances antigen presentation via major histocompatibility complex (MHC) molecules, and bridges innate and adaptive immunity. IFN-γ is indispensable in shaping Th1 immune responses and in the control of intracellular pathogens, including certain viruses, bacteria, and protozoa [30, 31].
Type III Interferons, also known as IFN-λ family, include IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4 [23]. These interferons signal through a receptor complex composed of IL-28Rα and IL-10Rβ, with expression restricted mainly to epithelial cells [32]. Their role is especially significant in mucosal antiviral defense, such as in the respiratory and gastrointestinal tracts, where they provide localized protection without the systemic inflammatory effects often associated with type I IFNs.
Although IFNs are classically recognized for their antiviral properties, their biological activities extend far beyond viral defense. They influence cell proliferation, apoptosis, and differentiation, making them key modulators of cancer surveillance and immunotherapy [32]. Furthermore, dysregulation of IFN signaling is implicated in autoimmune disorders, chronic viral persistence, and inflammatory diseases [17, 33, 34].
In summary, the IFN family represents a diverse but interconnected network of cytokines with specialized and overlapping functions. From the multiple isoforms of IFN-α to the unique reproductive role of IFN-τ and the immune-regulatory function of IFN-γ, these molecules are central to maintaining host defense and immune homeostasis [26, 35, 36]. Understanding the nuances of each IFN subtype continues to provide important insights into therapeutic strategies against infections, cancers, and immune-mediated diseases.

The role on IFN in BLV infection
Interferons (IFNs) play a central role in host immune defense against bovine leukemia virus (BLV) by orchestrating antiviral, immunomodulatory, and antiproliferative responses that restrict viral replication and disease progression [35]. As BLV establishes persistent infection through immune evasion, IFNs act as first-line mediators by upregulating interferon-stimulated genes, enhancing antigen presentation, and activating innate and adaptive immune pathways. However, BLV has evolved mechanisms to counteract IFN signaling, facilitating viral persistence and contributing to the onset of enzootic bovine leukosis.
Cytokine expression studies have revealed dynamic, stage-dependent immune modulation throughout BLV infection. Keefe et al. demonstrated that early infection is characterized by upregulation of IFN-associated and Th1-type cytokines reflecting an antiviral response aimed at limiting viral replication, whereas advanced stages, particularly in animals with persistent lymphocytosis or lymphoma, exhibit dysregulated cytokine expression, reduced IFN signaling, and a shift toward Th2 or regulatory cytokines that promote immune evasion and leukemogenesis [37]. Similarly, Yakobson et al. showed that animals mounting strong early IFN-mediated Th1 responses more effectively control viral replication and remain aleukemic, while animals with weaker IFN responses and stronger Th2 or regulatory activity are predisposed to persistent lymphocytosis, polyclonal B-cell expansion, and increased proviral load [38].
Interferon responsiveness not only shapes immune polarization but also affects BLV transcriptional regulation. Kiermer et al. identified an interferon regulatory factor (IRF) binding site within the U5 region of the BLV long terminal repeat (LTR), demonstrating that IFN-induced IRFs can paradoxically enhance BLV transcription independently of the viral transactivator Tax, thus promoting viral persistence. These observations highlight the dual nature of IFN signaling during BLV infection, functioning simultaneously as an antiviral mechanism and a potential facilitator of viral gene expression [39].
Multiple studies further support the importance of IFN-γ in determining infection outcomes. Using an experimental ovine model, Usui et al. reported that animals with high early IFN-γ expression exhibit significantly reduced BLV replication, lower proviral loads, and delayed or suppressed disease progression, whereas weak IFN-γ responses allow greater viral replication and the rapid establishment of persistent infection [40]. Consistent with these findings, Farias et al. demonstrated that cattle with low proviral loads express higher levels of Toll-like receptors, IFN-γ, and interleukin-12 (IL-12), indicating intact IFN-driven immunity, while animals with high proviral loads show decreased expression of these mediators and impaired antiviral activity [41]. In addition, Usuga-Monroy et al. observed significantly reduced IFN-γ mRNA expression in BLV-infected Holstein cattle with high proviral loads and persistent lymphocytosis, suggesting compromised Th1-type immunity and enhanced viral persistence [42]. Similarly, Marin-Flamand et al. found that animals with high proviral load and persistent lymphocytosis exhibit reduced expression of Th1 cytokines, particularly IFN-γ and IL-12, alongside increased levels of regulatory and Th2 cytokines, such as IL-10 and TGF-β [43]. This cytokine imbalance implies that diminished IFN-γ-mediated activity weakens antiviral immunity, while elevated immunosuppressive cytokines facilitate BLV persistence and disease progression.
Beyond their immunological role, IFNs also show therapeutic potential. Kohara et al. demonstrated that recombinant IFN-τ effectively suppresses BLV replication in vitro by reducing viral gene expression and proviral load and, in vivo, decreases viral replication and favorably modulates immune responses without the cytotoxicity associated with other IFN types [35]. Subsequent work by Sei-Ichi et al. confirmed that IFN-τ enhances antiviral immunity in naturally infected Japanese Black cattle by upregulating interferon-stimulated genes, increasing cellular immune activation, reducing proviral load, and shifting cytokine expression toward a Th1-dominant pattern, supporting its potential therapeutic or prophylactic value [36]. Furthermore, immune checkpoint targeting has recently emerged as an alternative approach to restore IFN-mediated antiviral activity. Borovikov et al. demonstrated that blockade of CTLA-4 and PD-1/PD-L1 pathways in BLV-infected cattle enhances T-cell activity and significantly increases IFN-γ production, suggesting that BLV exploits checkpoint pathways to suppress IFN-driven immunity [44].
Collectively, these findings demonstrate that IFNs, particularly IFN-γ, play a critical role in regulating host immune responses and limiting BLV replication; however, their activity progressively attenuates as infection progresses (Fig. 2). Animals with high proviral loads or persistent lymphocytosis consistently display reduced IFN-γ expression, impaired Th1 immunity, and cytokine polarization toward Th2 and regulatory phenotypes that promote viral persistence [45]. BLV also appears capable of hijacking host regulatory circuits, including IRF-dependent transcriptional activation and immune checkpoint pathways, to dampen IFN signaling [41]. Conversely, therapeutic modulation of IFN pathways, including recombinant IFN-τ administration or immune checkpoint blockade, can restore antiviral function, offering promising strategies to control BLV infection, disease progression, and transmission.

The dual role of IFN in HTLV-1 infection
Interferons (IFNs) are central immune mediators that activate antiviral pathways and shape adaptive immunity during retroviral infections; however, their efficacy is often compromised by viral immune evasion strategies [46, 47]. Type I IFNs (α/β) activate JAK–STAT signaling and stimulate ISG expression to suppress viral replication, while Type II IFN (IFN-γ) enhances cytotoxic T-cell and natural killer cell responses [26, 48]. The importance of IFN-γ during HTLV-1–driven oncogenesis was demonstrated by Mitra-Kaushik et al., who showed that IFN-γ-deficient HTLV-1 Tax-transgenic mice experienced accelerated tumor onset, dissemination, and mortality [49]. Tumors in IFN-γ-deficient mice exhibited increased IL-2 receptor-β and decreased ICAM-1 expression, along with enhanced angiogenesis, as evidenced by elevated CD31 staining and upregulated VEGF and tenascin C, while TNF-α and tissue inhibitor of matrix metalloproteinase-1 were downregulated, indicating that IFN-γ normally exerts angiostatic and tumor-suppressive activity.
The relationship between IFN signaling and HTLV-1 persistence has been examined in cell culture models. Moens et al. found that IFN-α treatment of HTLV-1–infected CD4⁺ T-cell lines activated STAT1/STAT2 and induced ISG expression, confirming intact interferon pathways, yet failed to reduce viral mRNA levels or induce cytotoxic effects, producing only modest post-transcriptional inhibition of p19 protein secretion [50]. Notably, IFN-α retained strong antiviral activity against HIV-1 in co-infected cells, suggesting that HTLV-1 exhibits virus-specific resistance to IFN-α. The complex role of IFN in HTLV-1–associated comorbidities was further illustrated by Satoh et al., who reported that HTLV-positive individuals show reduced therapeutic responsiveness to strongyloidiasis, linked to elevated IFN-γ and TGF-β1 signaling that disrupts immune control and impairs parasite clearance [51]. Additional studies have highlighted the limited capacity of IFN signaling to block early HTLV-1 transmission. Rizkallah et al. demonstrated that IFN-γ does not significantly restrict virus entry or dendritic-cell–mediated transmission to T-cells; rather, dendritic-cell maturation state is the primary determinant of viral susceptibility, with mature dendritic cells showing resistance compared to immature ones [52]. Host–virus interactions at the transcriptional level were further explored by Refaat et al., who reanalyzed transcriptional datasets to identify IFN-stimulated genes differentially expressed in HTLV-transformed cells [53]. These genes were associated with antiviral defense, immune regulation, and cell survival, indicating that IFN responses remain active but are selectively reshaped by HTLV-1 to support persistence and transformation.
More recently, Machado et al. demonstrated that IgG from HTLV-infected patients modulates cytokine production in immune cells from healthy donors by increasing IL-4 and IL-10 while reducing IFN-γ and IL-17 across T-cell and B-cell subsets [54]. This shift toward a Th2/regulatory profile dampens Th1 responses and weakens IFN-γ–mediated antiviral immunity, thereby supporting viral persistence and immunopathogenesis.
Overall, IFN responses play a dual and context-dependent role in HTLV-1 infection (Fig. 3). While IFN-mediated pathways stimulate antiviral immunity, cytotoxic function, and tumor angiostasis, HTLV-1 can evade IFN-driven antiviral restriction, exploit IFN-associated inflammation, and remodel cytokine signaling to favor immune dysregulation and leukemogenesis.
Viral proteins, host immune status, and secondary factors such as antibody-mediated cytokine modulation collectively shape disease outcome. A better understanding of these interactions will facilitate the development of therapeutic approaches that reinforce IFN’s antiviral capacity while minimizing contributions to chronic inflammation and disease progression.

In continue, we will review the diver’s interaction of IFN and HTLV in defining the outcome of infection.

HTLV onco-proteins interaction with IFN pathway
HTLV-1 infection profoundly modulates host immune responses through complex interactions between viral proteins and interferon (IFN) signaling, thereby balancing antiviral defense and immune dysregulation [55]. Tax expression in autoreactive T cells was shown by Takatsuka et al. to enhance CD80/CD86 expression in G14-Tax cells, an IL-2-dependent HTLV-1–negative CD4⁺CD8⁺ T-cell line established from an HTLV-1–infected rat, leading to vigorous proliferation of naïve rat T cells that became CD4⁺CD25⁺CTLA-4⁺ and produced IL-10 and IFN-γ [34].
In HBZ-transgenic mice, Mitagami et al. [56] demonstrated that chronic IFN-γ signaling promotes inflammation, abnormal T-cell proliferation, and lymphoma development, highlighting the paradoxical role of IFN-γ in driving disease despite its antiviral function [56]. Additionally, Diani et al. [57] showed that Tax engages host kinases IKKε and TBK1 to activate IFN-γ expression, illustrating how Tax can initially stimulate IFN-α responses while ultimately facilitating immune dysregulation and viral persistence [57]. Collectively, these studies demonstrate that Tax and HBZ regulate cytokine production, T-cell activation, and IFN pathways, enabling both immune activation and viral evasion. Tax induces IL-10- and IFN-γ-producing regulatory T-cell populations, while HBZ-driven chronic IFN-γ signaling promotes lymphomagenesis. Meanwhile, Tax-mediated IFN-I activation further reflects the paradoxical manipulation of IFN pathways that supports HTLV-1 persistence and disease progression.

HTLV can manipulate IRFs genes
HTLV has evolved sophisticated mechanisms to manipulate interferon regulatory factors (IRFs) and to circumvent antiviral immunity, thereby facilitating viral persistence and disease progression [58]. The HTLV-1 bZIP factor HBZ suppresses IRF-1 activity through dual mechanisms: binding its N-terminal domain to reduce DNA-binding capacity and inducing proteasome-dependent degradation, while also diminishing IRF-1–mediated apoptosis, thereby promoting infected cell survival [59]. HTLV-1 further disrupts IFN pathways through SOCS1, which is upregulated in infected CD4⁺ T cells and correlates with increased viral mRNA levels in HAM/TSP patients [46]. SOCS1 promotes proteasomal degradation of IRF3, impairing IFN-α/β signaling and ISG activation; its overexpression enhances HTLV-1 replication, whereas SOCS1 silencing restores IFN production and reduces viral replication (Fig. 4) [46].
Additional immune dysregulation is mediated through IRF4, which is strongly induced by Tax to promote infected T-cell survival, proliferation, and resistance to apoptosis, contributing to leukemogenesis [60]. In parallel, IRF4 was shown to activate the IL-15 receptor α promoter, enhancing T-cell proliferation and survival to support viral persistence [61]. These findings illustrate how Tax-driven IRF4 activation cooperates with host transcriptional networks to sustain infection and transformation (Fig. 4). Although type I IFNs are induced during infection, IFN signaling alone is insufficient to suppress HTLV replication; even when IFN-α stimulates ISGs and STAT signaling in infected T cells, antiviral effects remain modest, and dendritic cell maturation appears critical for controlling viral spread (Fig. 4). Taken together, these studies highlight coordinated viral strategies targeting IRF-1, IRF3, and IRF4 and exploiting IFN networks to enable immune evasion, abnormal T-cell growth, and HTLV-1-associated oncogenesis (Fig. 4).

Genetic variation in IFN axis can modified the outcome of HTLV infection
Host genetic variation significantly influences the outcome of HTLV infection by modulating interferon signaling pathways and immune responses [62]. Khouri et al. (2018) identified a genetic IFN/STAT1/FAS axis regulating CD4⁺ T stem cell memory and apoptosis, showing that dysregulation of this pathway in HTLV infection promotes abnormal T-cell survival and leukemogenesis [63]. In Queiroz et al. (2020), individuals carrying the SAMHD1 rs6029941 G allele exhibited higher proviral loads and reduced IFN-α levels, suggesting impaired IFN-mediated antiviral restriction through altered SAMHD1 regulation [64]. A 2024 study by Santana et al. found that TLR7 polymorphisms rs179008 and rs3853839 variably affected IFN-α output, with A/G allele combinations linked to enhanced IFN-α and reduced proviral load, underscoring the complex role of TLR7 genetic variation in antiviral immunity; however, these variants were not associated with HTLV-1-related disease (Fig. 4) [65].
Ahmed et al. (2025) demonstrated that individuals carrying the + 874 T allele of the IFN-γ SNP show elevated plasma IFN-γ levels and increased proviral load, reflecting heightened inflammation without clear discrimination between asymptomatic and symptomatic states, emphasizing a multifactorial disease process [33]. Similarly, Ferreira et al. (2025) reported that the TLR3 rs3775291 TT genotype correlates with increased IFN-α and TLR3 expression, reduced proviral load, and lower TNF-α/IL-6 levels, suggesting enhanced antiviral defense, although this polymorphism did not affect overall susceptibility or disease development [66]. In a recent systematic review and meta-analysis, Cuenca et al. (2025) examined IL-28B polymorphisms (rs8099917, rs12979860) and found that CC (rs12979860) and TT (rs8099917) genotypes were associated with increased IFN-λ3 production, potentially boosting antiviral immunity, though heterogeneity in study findings limited firm conclusions (Fig. 4) [67].
Collectively, these studies indicate that polymorphisms across IFN genes, receptors, signaling pathways, and restriction factors shape innate and adaptive immunity during HTLV infection. Variations affecting IFN/STAT signaling, TLR pathways, and antiviral factors influence T-cell survival, apoptosis, and viral control, contributing to heterogeneity in proviral load, immune dysfunction, and clinical progression (Fig. 4). This underscores the critical role of host genetic background in determining immune homeostasis, viral persistence, and disease outcomes in HTLV infection.

IFN alterations in HTLV associated diseases
IFN responses vary among HTLV-associated diseases and differ from those observed in cell lines or asymptomatic infection [68]. A systems biology investigation identified a distinct IFN-inducible signature in HTLV-associated myelopathy (HAM/TSP), marked by widespread upregulation of IFN-stimulated genes in blood and affected tissues, correlating with chronic immune activation, inflammation, and clinical severity [69]. Consistently, Kuroda et al. (1993) reported elevated cerebrospinal fluid IFN-γ in HAM/TSP, linking IFN-γ–driven inflammation to neural injury and disease progression [70].
In Kubota et al. (2000), higher proviral load correlated with increased HTLV-specific IFN-γ⁺ CD8⁺ T cells, indicating persistent antigen stimulation; however, despite strong cytotoxic responses, viral clearance was not achieved, contributing to immune exhaustion and disease progression [71]. IFN also participates in p38 MAPK–dependent pathology: Fukushima et al. (2005) demonstrated that p38 activation enhances IFN-γ production and HTLV expression in T cells, while its inhibition lowers both inflammatory and viral activity [72]. Blocking IL-2 receptor signaling similarly reduced IFN-γ release and HTLV transcription, revealing IL-2–dependent maintenance of inflammatory activation and viral persistence [73].
A strong pro-inflammatory profile in HAM/TSP was further supported by Bidkhori et al. (2020), who found higher levels of IFN-γ, IL-18, and IL-12 in patients than in carriers or controls, implicating these cytokines in neural tissue damage [74]. Similarly, Yamano et al. (2009) identified highly pro-inflammatory IFN-γ⁺ CCR4⁺ CD4⁺ CD25⁺ infected T cells that contribute to chronic inflammation while serving as viral reservoirs [75]. Espindola et al. (2015) observed a high IFN-γ/IL-10 ratio alongside persistent HTLV-infected T-cell clones, indicating a sustained inflammatory environment despite ineffective clearance [76]. In line with this, Neco et al. (2017) reported elevated CXCL9, CXCL10, IFN-γ, and TNF-α in HAM/TSP, with IFN-γ–driven chemokines amplifying CNS infiltration and damage [77].
Despite the induction of restriction factors, IFN often fails to eradicate infection. Leal et al. [78] showed that IFN-β upregulates antiviral factors ex vivo and in vivo, yet HTLV persists, highlighting viral evasion of IFN-mediated immunity [78]. Similarly, Mozhgani et al. [79] found that higher HTLV-1 proviral load and HBZ expression correlate with HAM/TSP severity, while IFN-λ3 helps modulate antiviral immunity but remains insufficient to stop disease progression [79].
Together, these studies underscore the paradoxical role of IFN in HTLV-associated neuroinflammatory disease (Fig. 3). Although IFN promotes antiviral defense through cytotoxic T-cell activation and restriction factor induction, persistent IFN signaling driven by viral proteins and pathways such as IL-2 and p38 MAPK drives chronic inflammation, immune-mediated neural damage, and disease progression. This dual function highlights the delicate balance between protective immunity and immunopathology in HTLV infection, where sustained IFN activity fails to clear the virus but contributes to neuroinflammation and tissue injury (Fig. 3).

Therapeutic approach of IFN in deltaretrovirus infection

IFN therapy in BLV infection
Imanishi et al. (1987) showed that type I and II IFNs markedly inhibit BLV-induced syncytium formation in vitro, reducing cell-to-cell viral transmission, while TNF displayed weaker suppressive activity [80]. Further supporting the antiviral function of interferons, Sentsui et al. (2001) demonstrated that recombinant bovine IFN-γ suppresses BLV replication by decreasing viral RNA expression, limiting virus production, and enhancing antiviral immunity through ISG upregulation [81].
Murakami et al. (2004) observed that IFN-γ treatment of chronically infected cattle increased circulating γδ T cells, correlating with enhanced cellular immunity and potential viral suppression, suggesting a role for IFN-γ in strengthening antiviral cytotoxic responses during persistent infection [82]. Similarly, Usui et al. (2007) found that early IFN-γ induction in experimentally infected sheep was associated with reduced viral replication, lower proviral load, delayed disease progression, and improved cytotoxic T-cell–mediated clearance of infected cells [40].
More recently, Mukantayev et al. (2024) reported that combining CTLA-4 and PD-L1 blockade with IL-15 immunotherapy enhanced T-cell proliferation and cytotoxicity, including IFN-producing populations, leading to improved control of BLV-infected cells and demonstrating the therapeutic benefit of augmenting IFN responses [83]. Collectively, these studies indicate that IFNs, particularly IFN-γ, help control BLV by limiting syncytium formation, reducing viral RNA levels, promoting ISG expression, and activating cytotoxic lymphocytes; moreover, strategies that boost IFN-mediated immunity can further enhance viral suppression and slow disease progression.

IFN therapy in HTLV infection
Despite the BLV, the therapeutic effects of IFN have been more extensively investigated in HTLV and its associated diseases. In 2015, Abad-Fernandez et al. explored the effect of interferon-alpha therapy on HTLV-2 viral load in co-infected patients [84]. The study found that patients who received interferon-alpha/ribavirin-based treatment for HCV exhibited a significant reduction in cell-associated HTLV-2 DNA, indicating a decreased viral burden [84]. Interestingly, a similar reduction in HTLV-2 DNA was observed in patients who spontaneously cleared HCV RNA, suggesting that interferon-alpha–mediated immune activation contributes to controlling HTLV-2 replication [84]. These studies were done in three different stages: in vitro, ATLL, and HAM/TSP patients.

In vitro study
Koyama et al. (1990) demonstrated that recombinant IFN-α2, IFN-β, and IFN-γ suppress HTLV-1 replication by reducing viral gene expression and protein production, while also inhibiting ATL cell proliferation, with IFN-α2 showing the strongest antiviral effect and IFN-γ most potently restricting cell growth [85]. Similarly, D’Onofrio et al. (1992) reported that IFN-α, IFN-β, and IFN-γ individually reduced viral protein expression and early HTLV-1 replication, whereas combined IFN therapy produced a stronger synergistic antiviral effect through induction of interferon-stimulated genes and enhancement of host immunity [86]. A subsequent study found that IFN-α/β combined with prostaglandin A1 (PGA1) more effectively inhibited HTLV-1 gene expression and replication in primary cord blood mononuclear cells than IFN alone, thereby reducing early viral persistence [87].
Combination therapies were later examined with anticancer agents. El-Sabban et al. (2000) found that IFN-α plus arsenic induced apoptosis in HTLV-1–transformed cells by suppressing Tax expression and reversing NF-κB activation, thereby inhibiting proliferation and oncogenic signaling [88]. Nasr et al. (2003) showed that arsenic alone rapidly inhibited NF-κB–dependent transcription by stabilizing IκB, whereas arsenic plus IFN-α provided delayed yet broad repression of cell-cycle genes, accompanied by proteasome-mediated Tax degradation and apoptosis in ATLL cells [89]. Mahieux et al. (2005) confirmed selective induction of apoptosis in HTLV-1/2-infected or transformed cells following arsenic/IFN-α therapy, linked to Tax degradation and NF-κB disruption; in vivo, this combination therapy suppressed leukemic growth in mouse models [90]. Brown et al. (2007) further demonstrated that adding emodin and DHA enhanced As₂O₃/IFN-α–mediated cell death via ROS generation and inhibition of Akt and AP-1 survival pathways, reinforcing IFN-α’s cooperative role in targeting HTLV-transformed cell viability [91].
Regarding IFN combined with antiretrovirals, Bazarbachi et al. (2000) reported that AZT, IFN-α, or both lacked direct cytotoxic activity against leukemic cells in vitro and did not inhibit proliferation, apoptosis, or cell-cycle progression, despite clinical remission in treated ATLL patients [92]. In contrast, Kinpara et al. (2013) observed that IFN-α alone inhibited HTLV-1 gene expression, viral protein production, and cell-cycle progression, while its combination with AZT enhanced antiviral efficacy by activating p53-mediated apoptosis, thereby eliminating infected cells and limiting leukemia progression [93]. These findings collectively indicate that IFN-α can reduce proviral load by suppressing viral replication, restricting cell proliferation, and, when combined with agents such as AZT or arsenic, inducing apoptosis in infected or transformed cells, underscoring its therapeutic potential against HTLV-1/HTLV-2–associated disease (Table 1).

IFN therapy in ATLL patients
Broniscer et al. (1996) described a clinical case in which combined interferon-α and zidovudine treatment in HTLV-1–associated adult T-cell leukemia markedly reduced circulating leukemic cells and improved hematologic parameters, likely through suppression of viral gene expression, inhibition of infected-cell proliferation, and reverse-transcription blockade, ultimately promoting apoptosis and achieving sustained remission [94]. In 2005, Mone et al. reported that alemtuzumab induced a durable complete hematologic response and significantly lowered viral load in a patient with ATLL refractory to AZT/IFN-α therapy, demonstrating that CD52-directed monoclonal antibody therapy can overcome resistance to standard regimens [95].
A cohort study from northeastern Iran showed that ATLL patients displayed significantly higher HTLV-1 proviral loads and plasma VEGF concentrations than asymptomatic carriers and healthy individuals, and treatment with AZT/IFN-α led to substantial reductions in proviral load (≈ 48.2 → 18.3 copies/100 cells) and VEGF levels (≈ 76.3 → 44.8 pg/mL), supporting both antiviral and anti-angiogenic activity and correlating with good clinical responses and improved survival [96]. Macchi et al. (2017) further demonstrated that AZT/IFN-α therapy suppresses HTLV-1 reverse transcriptase activity measured in cultured PBMCs from ATLL patients, implicating active inhibition of viral replication and suggesting that RT activity may serve as a predictive virological marker of treatment response [97].
Collectively, these findings confirm the therapeutic relevance of IFN-based regimens for controlling viral replication and leukemic burden in ATLL, but also indicate that clinical responses may be limited in some cases, necessitating alternative strategies such as monoclonal antibodies or combination therapies to manage refractory disease (Table 1).

IFN therapy in HAM/TSP patients
Interferon-based therapy has shown consistent clinical and immunological benefits in HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP). Kuroda et al. first evaluated IFN-α combined with high-dose IVGG in HAM patients, reporting that IVGG alone (10 g/day or 400 mg/kg/day for 5 days) improved spastic paraparesis in 10/14 patients for > 3 weeks, while IFN-α at 3.0 × 10^6 IU/day for 28 days improved nearly two-thirds of patients in mixed trial designs [98]. Similarly, Shibayama et al. demonstrated that IFN-α improved motor and neurological symptoms, reduced spontaneous proliferation of HTLV-1–infected lymphocytes, decreased proviral load, and modulated T-cell activation markers [99].
Randomized double-blind clinical studies confirmed that daily intramuscular IFN-α provided significant neurological improvement, especially at higher doses, and benefits sometimes persisted beyond treatment [100, 101]. Mechanistically, IFN-α suppressed proviral load, decreased infected lymphocyte proliferation, and modulated inflammatory T-cell responses. Long-term therapy also maintained suppression of spontaneous CD4⁺ T-cell clonal proliferation after treatment cessation [102].
Sustained neurological improvement with reduced immune activation was further supported by two-year systemic IFN-α treatment reported by Gazzola et al. [103]. Moens et al. found that ascorbic acid exerted stronger ex vivo antiproliferative and immunomodulatory effects than IFN-α, though IFN-α still significantly controlled T-cell proliferation, immune activation, and inflammatory responses [50]. Rafatpanah et al. similarly showed IFN-α–induced clinical improvement, reduced proviral load, and modulation of lymphocyte proliferation and T-cell activation markers [104].
Therapeutic benefit was also reported with interferon β-1a, which improved motor function and spasticity via immune modulation [105]. Combination therapy using prednisolone, pegylated IFN, and sodium valproate enhanced motor and spastic outcomes while reducing proviral load and Tax/HBZ expression [106].
Additional studies demonstrated immunomodulatory outcomes following IFN therapy, including improved disease outcome and altered T-cell phenotype [107], reduced proviral load with Th1→balanced Th1/Th2 shift [108], and partial normalization of the T-cell Vβ repertoire with reduced clonal expansion linked to clinical improvement [109]. Furthermore, IFN-α reduced CSF CXCL10 levels, which correlated with improved neurological outcomes, highlighting its role in suppressing inflammatory chemokines and limiting immune-mediated neuronal damage [110].
Collectively, these studies (Table 1) demonstrate that IFN-α improves motor and neurological function often sustained during prolonged therapy while exerting antiviral effects by reducing proviral load, inhibiting spontaneous proliferation of infected clones, and suppressing viral gene expression (Tax, HBZ). Concurrent immune modulation includes rebalancing Th1/Th2 responses, reducing CXCL10, normalizing T-cell receptor repertoires, and altering activation phenotypes. These combined antivirals and immunoregulatory effects support IFN-α as a principal therapeutic strategy for HAM/TSP.

Conclusion and future directions
Interferons play a central yet paradoxical role in deltaretrovirus infections. In both HTLV-1 and BLV, IFNs initiate robust antiviral responses by inducing ISGs, activating cytotoxic immunity, and suppressing viral replication. However, these viruses have evolved sophisticated evasion strategies. HTLV-1 manipulates the IFN pathways via viral proteins such as Tax and HBZ, induces SOCS1, and modulates IRFs, whereas BLV exploits immune checkpoints and cytokine imbalance to suppress IFN-γ activity. As a result, IFN signaling, while protective, also contributes to chronic inflammation, immune exhaustion, and, in the case of HTLV-1, leukemogenesis and neuroinflammation.
Therapeutically, IFN-based strategies have shown partial success. In BLV, recombinant IFN-τ and IFN-γ demonstrate antiviral and immunomodulatory effects in vitro and in vivo, but economic and practical barriers in livestock limit their application. In HTLV-1 infection, IFN-α alone has limited efficacy, but combination regimens with zidovudine, arsenic trioxide, or checkpoint inhibitors improve patient outcomes in both ATLL and HAM/TSP. Nevertheless, resistance, incomplete responses, and toxicity remain significant challenges.
Future research should prioritize three directions. First, comparative studies of BLV and HTLV-1 will help clarify why these viruses differ in their susceptibility to IFN-mediated control, offering insights into host-pathogen interactions. Second, greater emphasis on host genetics, including IFN-axis polymorphisms and restriction factors, may uncover predictive biomarkers for therapy response and disease progression. Finally, novel therapeutic strategies should aim to harness IFN’s antiviral properties while limiting its pathogenic effects, potentially through targeted delivery, modulation of downstream ISGs, or rational combinations with antiretroviral and immunomodulatory agents.
Overall, IFNs remain a cornerstone of the antiviral defense against deltaretroviruses, but their clinical application requires careful balancing of protective and pathological effects. Bridging mechanistic insights with translational approaches will be essential to design next-generation IFN-based therapies that effectively control viral persistence while minimizing immune-mediated damage.