Background Glioblastoma remains one of the most lethal malignancies, characterized by rapid recurrence, profound intratumoral heterogeneity, and a highly immunosuppressive microenvironment.Among immunotherapeutic strategies, peptide-based vaccines have attracted attention for their safety, specificity, and capacity to elicit tumor-directed T cell responses. Over the past two decades, several platforms targeting tumor-associated or tumor-specific antigens, including EGFRvIII, WT1, and survivin, have advanced into clinical trials. While early-phase studies demonstrated immunogenicity and occasional survival benefits, phase III trials have largely failed to confirm durable efficacy, underscoring the challenges posed by the ongoing complexity of tumor evasion mechanisms among which down regulation of MHC (HLA) expression in tumor cells, lack or reduced tumor antigen expression and a suppressive tumor microenvironment certainly play a role. Main body As far as tumor antigens, recent insights also question the centrality of neoantigens, highlighting instead the immunogenicity of shared tumor-associated antigens, which may provide a more reliable foundation for broadly applicable vaccines in GBM. A major barrier to efficacy remains impaired antigen presentation, particularly the downregulation of MHC-II pathways. In this context, strategies leveraging the transcriptional activator CIITA to restore MHC-II expression hold promise both for reprogramming GBM cells into effective antigen-presenting cells and for the isolation of new families of MHC class II-bound peptides relevant for the triggering of tumor-specific CD4+ T cells. Conclusion This new approach could pave the way for next-generation peptide vaccines, particularly when integrated with combinatorial modalities such as checkpoint inhibitors, myeloid-targeted therapies, or oncolytic viruses.

Introduction:HLA-G is a non-classical major histocompatibility complex class I molecule with potent immunosuppressive activity and is increasingly recognized as an immune-checkpoint axis in cancer. Its prognostic significance in non-small cell lung cancer (NSCLC), particularly in relation to PD-L1 expression and CD8+ tumor-infiltrating lymphocytes (TILs), remains incompletely defined. Methods:We retrospectively analyzed 314 surgically resected NSCLCs assembled in tissue microarrays and stained for HLA-G, PD-L1, and CD8. HLA-G and PD-L1 were scored as positive when ≥1% of tumor cells showed membranous staining, whereas CD8+ TIL density was digitally quantified and dichotomized using the cohort median (≥575 cells/mm²). Associations with clinicopathological variables and outcomes were assessed by Kaplan-Meier analysis and multivariable Cox regression. Results:HLA-G was expressed in 50 of 314 tumors (16%), PD-L1 in 106 of 314 (33.8%), and high CD8 density in 160 of 314 (51%). In HLA-G-negative tumors, high CD8+ TIL density was associated with significantly prolonged disease-free survival (DFS) and overall survival (OS). In the overall cohort, the combined HLA-G-negative/CD8-high phenotype retained independent favorable prognostic significance for both DFS and OS. By contrast, CD8 density did not significantly stratify outcome in HLA-G-positive tumors, although these subgroup analyses were limited by small sample size. Discussion:In combined biomarker analyses, the favorable prognostic effect of CD8+ TILs in PD-L1-negative tumors was maintained only when HLA-G was also absent. Within the PD-L1-positive/HLA-G-negative subgroup, high CD8 density was independently associated with improved DFS but not OS. Integrating HLA-G with PD-L1 and CD8 assessment may refine prognostic stratification and help identify patients who could benefit from HLA-G-targeted strategies, alone or in combination with PD-1/PD-L1 blockade.

Human T-cell leukemia virus-1 (HTLV-1) is the etiological agent of a series of chronic inflammatory diseases such as HTLV-associated myelopathy/Tropical spastic paraparesis (HAM/TSP), uveitis, dermatitis, and pneumonitis, and, importantly, of a T-cell lymphoproliferative neoplasm designed adult T-cell leukemia/lymphoma (ATL). Two viral proteins, Tax-1 and HBZ, are crucially involved in HTLV-1 infectivity and in ATL by altering key pathways of cell homeostasis. A fundamental distinction between the expression of the two oncoproteins exists, witnessed by the fact that Tax-1 is expressed in early phases of HTLV-1 infectivity and ATL onset but may be lost in a substantial number of established ATL, whereas HBZ is always expressed in all phases of HTLV-1 infection and in all ATL. Additionally, while Tax-1 can be localized both in the cytoplasm and nucleus in all cases of disease, recent evidence indicate that HBZ is localized solely in the cytoplasm in cells of HTLV-1-infected individuals, asymptomatic carriers (AC) and patients suffering from HAM/TSP. Importantly, ATL instead marks a progressive dislocation of HBZ in the nucleus. Thus, both the expression and the subcellular localization of HBZ represent distinctive elements in the process of HTLV-1-associated pathology. Within this frame, recent studies point to a very important involvement of HBZ in disarranging the homeostasis of the cell not only at the transcriptional but most importantly at the post-transcriptional level as a result of the interaction with crucial factors regulating RNA splicing and stability. These recent aspects of the HBZ biology will be discussed for their implication in HTLV-1-mediated oncogenesis.

[This corrects the article DOI: 10.3389/fimmu.2026.1732852.].

Human T-cell Leukemia Virus type 1 (HTLV-1) drives Adult T-cell Leukemia/Lymphoma (ATLL) through sustained expression of the viral oncoprotein HBZ. Although HBZ is known to reshape host transcriptional programs, its role in post-transcriptional regulation in ATLL remains poorly understood. Here, we uncover a mechanism by which HBZ reprograms circular RNA (circRNA) biogenesis to support leukemic cell survival. Comprehensive circRNA profiling across ATLL subtypes revealed extensive circRNA remodeling, with distinct signatures associated with aggressive ATLL subtypes. Among these, circAFF2(3) is markedly upregulated in aggressive ATLL, and functional analyses show that its expression enhances, whereas its silencing reduces, the survival of HTLV-1-transformed T cells. Mechanistically, we show that HBZ interacts with the RNA helicase DHX9 and inhibits its helicase activity at intronic double-stranded RNA structures flanking circularized exons. Using both endogenous and synthetic circRNAs, we demonstrate that this inhibition allows RNA duplexes to persist, thereby promoting back-splicing and the accumulation of DHX9-sensitive circRNAs, including circAFF2(3). Together, these findings reveal that HTLV-1 hijacks host RNA helicase activity to reprogram circRNA biogenesis, identifying the HBZ-DHX9 axis as a novel post-transcriptional mechanism contributing to ATLL development.

Glioblastoma (GBM) is a highly malignant brain tumor with poor outcome, despite current therapies. CIITA-modified tumor cells, capable of presenting antigens via MHC-II, show promise in eliciting effective antitumor immune responses. The efficacy of the CIITA-based vaccination strategy has been previously demonstrated using the GL261 murine GBM model. This study aimed at verifying whether a different GBM model, the CT-2A cells, more closely resembles human GBM, could follow the same rule and importantly share cross immunity with GL261. To assess tumor growth and immune response, immunocompetent mice were injected intracranially with either CT-2A or CIITA-modified CT-2A (CT-2A-CIITA) cells, and brain tissues were examined histologically. Additionally, mice vaccinated with GL261-CIITA cells were subsequently challenged with parental CT-2A cells in the opposite hemisphere, followed by immunohistochemical analysis of brain tissues. Results indicated that CT-2A-CIITA cells were either rejected or exhibited delayed tumor growth in immunocompetent mice. Furthermore, mice previously vaccinated with GL261-CIITA cells demonstrated efficient rejection of CT-2A tumors, suggesting the induction of cross-protective immunity. This immune response was associated with a shift from an immunosuppressive to an immunogenic tumor microenvironment, implying the development of adaptive immunity against shared tumor antigens. In conclusion, these findings support the broader applicability of CIITA-based vaccination against GBM and provide the first evidence of shared immunogenic antigens between two distinct murine GBM models. This discovery opens avenues for identifying common tumor antigens through immunopeptidomics, which could inform future immunotherapeutic strategies for glioblastoma.

The different susceptibility to HIV-1 infection in U937 cells—permissive (Plus) or nonpermissive (Minus)—is linked to the expression in Minus cells of interferon (IFN)-γ inducible antiviral factors such as tripartite motif-containing protein 22 (TRIM22) and class II transactivator (CIITA). CIITA interacts with Cyclin T1, a key component of the Positive-Transcription Elongation Factor b (P-TEFb) complex needed for the efficient transcription of HIV-1 upon interaction with the viral transactivator Tat. TRIM22 interacts with CIITA, recruiting it into nuclear bodies together with Cyclin T1. A 50 kDa Cyclin T1 was found only in Minus cells, alongside the canonical 80 kDa protein. The expression of this truncated form remained unaffected by proteasome inhibitors but was reduced by IFNγ treatment. Unlike the nuclear full-length protein, truncated Cyclin T1 was also present in the cytoplasm, and this subcellular localization correlated with its capacity to inhibit Tat-mediated HIV-1 transcription. The 50 kDa Cyclin T1 in Minus cells likely contributes to their non-permissive phenotype by acting as a dominant negative factor, disrupting P-TEFb complex formation and function. Its reduction upon IFNγ treatment suggests a regulatory loop by which its inhibitory role on HIV-1 replication is then exerted by the IFNγ-induced CIITA, which binds to the canonical Cyclin T1, displacing it from the P-TEFb complex.

Oral Squamous Cell Carcinoma (OSCC) is the most common malignant tumor of the oral cavity. Despite recent advances in the field of oral cancer therapy, including the introduction of immunotherapeutic approaches, the 5-year survival rate remains steadily assessed around 50%. Thus, there is an urgent need for new therapeutic strategies. After the characterization of the immune phenotype of three human OSCC cell lines (CAL-27, SCC-25, and SCC-4) and one mouse OSCC cell line (MOC2) showing their similarities to resected patient tumors, we explored for the first time an experimental preclinical model of therapeutic vaccination with mouse OSCC MOC2 cell line stably expressing MHC class II antigens after CIITA gene transfection (MOC2-CIITA). Mice injected with MOC2-CIITA reject or strongly retard tumor growth; more importantly, vaccinated animals that fully reject MOC2-CIITA tumors display anti-tumor immunological memory protective against challenge with parental MOC2 tumor cells. Further experiments of adoptive cell transfer or in vivo cell depletion show that both CD4+ and CD8+ T lymphocytes prove fundamental in tumor rejection. This unprecedented approach for oral cancer opens the way for possible future translation of novel immunotherapeutic strategies to the human setting for the treatment of this tumor.

Abstract Background Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults with the lowest survival rates five years post-diagnosis. Oncolytic viruses (OVs) selectively target and damage cancer cells, and for this reason they are being investigated as new therapeutic tools also against GBM. Methods An oncolytic herpes simplex virus type 1 (oHSV-1) with deletions in the γ34.5 neurovirulence gene and the US12 gene, expressing enhanced green fluorescent protein (EGFP-oHSV-1) as reporter gene was generated and tested for its capacity to infect and kill the murine GL261 glioblastoma (GBM) cell line. Syngeneic mice were orthotopically injected with GL261cells. Seven days post-implantation, EGFP-oHSV-1 was administered intratumorally. Twenty-one days after parental tumor challenge in the opposite brain hemisphere, mice were sacrified and their brains were analysed by immunohistochemistry to assess tumor presence and cell infiltrate. Results oHSV-1 replicates and induces cell death of GL261 cells in vitro. A single intracranial injection of EGFP-oHSV-1 in established GL261 tumors significantly prolongs survival in all treated mice compared to placebo treatment. Notably, 45% of treated mice became long-term survivors, and rejected GL261 cells upon rechallenge in the contralateral brain hemisphere, indicating an anamnestic antitumoral immune response. Post-mortem analysis revealed a profound modification of the tumor microenvironment with increased infiltration of CD4 + and CD8 + T lymphocytes, intertumoral vascular collapse and activation and redistribution of macrophage, microglia, and astroglia in the tumor area, with the formation of intense fibrotic tissue suggestive of complete rejection in long-term survivor mice. Conclusions EGFP-oHSV1 demonstrates potent antitumoral activity in an immunocompetent GBM model as a monotherapy, resulting from direct cell killing combined with the stimulation of a protective adaptive immune response. These results open the way to possible application of our strategy in clinical setting.

AbstractThe 30th workshop of the HTLV European Research Network (HERN) was held in Madrid on September 15–16, 2023. Over fifty researchers from Europe and America convened for a two-day conference to update and discuss basic science, epidemiology, clinical management and therapeutics for patients with HTLV-1 infection. Scientific topics addressed included new estimates for HTLV-1 in Europe; impact of antenatal screening on mother-to-child HTLV-1 infections; new insights into the molecular epidemiology of HTLV-1; reports of elite controllers for HTLV-1 infection; role of antiretrovirals as HTLV-1 pre-exposure prophylaxis; and prospects for a HTLV-1 vaccine. The group agreed to submit a formal request to WHO for increasing the global surveillance and awareness of HTLV-1. This viral infection is a potentially life-threatening, neglected condition with neither treatment nor vaccine. At this time, expanding HTLV-1 screening is the most effective way to reduce viral dissemination.

Background: To date, there are no data regarding the mucosal immune response after the BNT162b2-booster vaccination.Methods: Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose and after two weeks. Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle. Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva. Findings: After eight months from the second dose, IgG decreased in both serum and saliva. Consistently, serum IgA decreased; however, salivary IgA increased, indicating a delayed activation of mucosal immunity. The booster elicited higher titres of both IgG and IgA when compared with the primary cycle, in both serum and saliva. Moreover, the booster re-established the neutralizing activity in the serum, not only against the Wuhan wild-type antigen but also against the variants. By contrast, the salivary neutralizing activity was high against the Wuhan antigen, but decreased against the variants, especially against the Omicron variant.Interpretation: The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron variant. Funding: This work was funded by the Department of Medicine and Surgery, University of Insubria, and supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020).Declaration of Interests: None to declare.Ethics Approval Statement: The clinical protocol for sample and data collection was approved by the Institutional Ethics Committee (Comitato Etico dell’Insubria, n° 165/2020).

Although the safety and efficacy of COVID-19 vaccines in older people are critical to their success, little is known about their immunogenicity among elderly residents of long-term care facilities (LTCFs). A single-center prospective cohort study was conducted: a total IgG antibody titer, neutralizing antibodies against Wild-type, Delta Plus, and Omicron BA.2 variants and T cell response, were measured eight months after the second dose of BNT162b2 vaccine (T0) and at least 15 days after the booster (T1). Forty-nine LTCF residents, with a median age of 84.8 ± 10.6 years, were enrolled. Previous COVID-19 infection was documented in 42.9% of the subjects one year before T0. At T1, the IgG titers increased up to 10-fold. This ratio was lower in the subjects with previous COVID-19 infection. At T1, IgG levels were similar in both groups. The neutralizing activity against Omicron BA.2 was significantly lower (65%) than that measured against Wild-type and Delta Plus (90%). A significant increase of T cell-specific immune response was observed after the booster. Frailty, older age, sex, cognitive impairment, and comorbidities did not affect antibody titers or T cell response. In the elderly sample analyzed, the BNT162b2 mRNA COVID-19 vaccine produced immunogenicity regardless of frailty.

Human nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key molecules for the homeostasis of the immune system. They are all characterized by a common backbone structure (the STAND ATPase module consisting in a nucleotide-binding domain (NBD), an helical domain 1 (HD1) and a winged helix domain (WHD), used by both prokaryotes and eukaryotes as defense mechanism. In this review, we will focus on the MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene expression and the founding member of NLR. Although a consistent part of the described NLR family components is often recalled as innate or intrinsic immune sensors, CIITA in fact occupies a special place as a unique example of regulator of both intrinsic and adaptive immunity. The description of the discovery of CIITA and the genetic and molecular characterization of its expression will be followed by the most recent studies that have unveiled this dual role of CIITA, key molecule in intrinsic immunity as restriction factor for human retroviruses and precious tool to induce the expression of MHC-II molecules in cancer cells, rendering them potent surrogate antigen presenting cells (APC) for their own tumor antigens.

Supplementary Data from Phase I/II Multicenter Trial of a Novel Therapeutic Cancer Vaccine, HepaVac-101, for Hepatocellular Carcinoma

Glioblastoma is the most malignant tumor of the central nervous system. Current treatments based on surgery, chemotherapy, and radiotherapy, and more recently on selected immunological approaches, unfortunately produce dismal outcomes, and less than 2% of patients survive after 5 years. Thus, there is an urgent need for new therapeutic strategies. Here, we report unprecedented positive results in terms of protection from glioblastoma growth in an animal experimental system after vaccination with glioblastoma GL261 cells stably expressing the MHC class II transactivator CIITA. Mice injected with GL261-CIITA express de novo MHC class II molecules and reject or strongly retard tumor growth as a consequence of rapid infiltration with CD4+ and CD8+ T cells. Importantly, mice vaccinated with GL261-CIITA cells by injection in the right brain hemisphere strongly reject parental GL261 tumors injected in the opposite brain hemisphere, indicating not only the acquisition of anti-tumor immune memory but also the capacity of immune T cells to migrate within the brain, overcoming the blood-brain barrier. GL261-CIITA cells are a potent anti-glioblastoma vaccine, stimulating a protective adaptive anti-tumor immune response in vivo as a consequence of CIITA-driven MHC class II expression and consequent acquisition of surrogate antigen-presenting function toward tumor-specific CD4+ Th cells. This unprecedented approach for glioblastoma demonstrates the feasibility of novel immunotherapeutic strategies for potential application in the clinical setting.

Abstract Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. Patients and Methods: A total of 82 patients with very early- to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints. Results: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against ≥1 vaccinated HLA class I tumor-associated peptide (TAA) and ≥1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. Conclusions: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I– and class II–restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.

Abstract Background Although immunotherapies represent an encouraging approach against cancer, to date none translated to the clinical benefit in Glioblastoma (GBM). One aspect contributing to this failure is the highly immunosuppressive GBM microenvironment. Our approach to overcome immunosuppression is to increase anti-tumor immune responses via adenovirus (AdV)-mediated delivery of the MHC-II Transactivator (CIITA) gene. CIITA-induced MHC-II expression is anticipated to convert GBM cells into surrogate antigen presenting cells able to prime T helper cells, therefore promoting CD4+ and CD8+ mediated immunity. Material and Methods We generated AdVs containing wild type CIITA (Ad-CIITA) using a replication-defective serotype5 adenoviral backbone. AdVs containing a mutated, non-functional version of CIITA (Ad-CIITA mutant) and an empty CMV promoter (Ad-null) were used as controls. AdV-mediated MHC-II expression was monitored at mRNA, protein and cell surface level. For the functional assessment of anti-tumor immune responses, we developed an advanced human GBM organoid model system consisting of tumor organoids co-cultured with either human peripheral blood mononuclear cells (PBMCs) or isolated CD3+ T cells. T cell mediated tumor cell killing was monitored over time via live cell imaging and flow cytometry. Results We successfully constructed and produced a CIITA-armed AdV that induces MHC-II expression in infected GBM cells, indicating the efficient expression of transcriptionally active CIITA for at least six days post infection. In immunocompetent human GBM organoids, Ad-CIITA infection of tumor cells led to prominent organoid disruption and tumor cell death, an effect that was not observed in the absence of PBMCs or CD3+ T cells. Tumor organoids infected with Ad-CIITA mutant remained intact, demonstrating the implication of cell surface MHC-II molecules in the observed phenotype. Conclusion Our results demonstrate that AdV-mediated delivery of CIITA is a promising strategy to increase T cell mediated immunity against glioblastoma.

Human T cell leukemia virus-1 (HTLV-1) is the causative agent of a severe cancer of the lymphoid lineage that develops in 3-5% of infected individuals after many years. HTLV-1 infection may also induce a serious inflammatory pathology of the nervous system designated HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Two virus-encoded proteins, the viral transactivator Tax-1 and the HTLV-1 basic leucine-zipper factor HBZ, are strongly involved in the oncogenic process. Tax-1 is involved in initial phases of the oncogenic process. Conversely, HBZ seems to be involved in maintenance of the neoplastic state as witnessed by the generation of leukemic/lymphomatous phenotype in HBZ transgenic mice and the persistent expression of HBZ in all phases of the oncogenic process. Nevertheless, the intimate molecular and cellular mechanism mediated by the two viral proteins, particularly HBZ, in oncogenesis still remain elusive. An important step toward the complete comprehension of HBZ-associated oncogenicity is the clarification of the anatomical correlates of HBZ during the various phases of HTLV-1 infection to development of HTLV-1-associated inflammatory pathology and ultimately to the establishment of leukemia. In this review, I will summarize recent studies that have established for the first time a temporal and unidirectional expression of HBZ, beginning with an exclusive cytoplasmic localization in infected asymptomatic individuals and in HAM/TSP patients and ending to a progressive cytoplasmic-to-nuclear transition in leukemic cells. These results are framed within the present knowledge of HTLV-1 infection and the future lines of research that may shed new light on the complex mechanism of HTLV-1- mediated oncogenesis.

Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.