Atae Utsunomiya

Human T‑cell leukemia virus type 1 (HTLV‑1) is a retrovirus that spreads primarily through cell‐to‐cell transmission. Occupational transmission of HTLV‐1 by needlestick injury is considered exceedingly rare, with no reported molecularly confirmed cases. We report two healthcare workers who experienced accidental needlestick injuries while caring for patients seropositive for HTLV‑1 and subsequently seroconverted. Full‑length HTLV‑1 proviral sequencing revealed complete nucleotide identity between source patients and infected nurses. These strains belonged to the HTLV‐1 subtype 1a Japanese subgroup but were distinct from 315 previously registered strains. Proviral integration site analysis demonstrated nonoverlapping integration profiles between source patients and healthcare workers, providing direct evidence of de novo HTLV‑1 infection rather than expansion of transferred infected cells. Longitudinal analysis in one case showed dynamic clonal turnover between 5 and 14 months after transmission; > 90% of infected‐cell clones were replaced, although the proviral load remained stable and low. Serological profiling revealed transiently elevated immunoglobulin M responses to Gag p19 peptides during early infection, followed by gradual immunoglobulin G maturation. These findings provide the first molecular confirmation of HTLV‑1 transmission via needlestick injury resulting in de novo infection, revealing an under‐recognized occupational exposure route and supporting reconsideration of post‐exposure testing strategies, particularly in endemic regions.

Purpose Physical function frequently declines after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the influence of disease status and general condition at the time of transplantation on longitudinal functional changes remains unclear. Methods This retrospective study included 135 adult patients with hematological malignancies who underwent their first allo-HSCT and completed physical function assessments before transplantation and at discharge. Handgrip strength and 6-min walk distance (6MWD) were evaluated. Patients were stratified according to disease status (complete remission [CR] vs. non-CR) and general condition (performance status [PS]). Results Both handgrip strength and 6MWD decreased significantly after transplantation in all groups. No significant differences in functional changes were observed between the CR and non-CR groups. In contrast, patients with poor PS at transplantation tended to show a greater decline in 6MWD than those with good PS. Multiple regression analysis identified PS at transplantation, age, sex, and change in the hemoglobin level as significant factors associated with changes in 6MWD. Conclusion Pre-transplant PS was associated with a greater post-transplant decline in endurance capacity, regardless of disease status. PS may serve as a practical clinical indicator for identifying patients at higher risk of physical function deterioration and guiding early targeted rehabilitation interventions.

Summary: Although adult T‐cell leukaemia/lymphoma (ATL) has a higher burden in certain world regions, outcomes have not been directly compared across regions. We conducted a multicentre cohort study comparing the distribution of ATL subtypes and overall survival (OS) across 1090 adults (≥18 years) diagnosed with ATL during 2000–2023 in Japan ( n = 366), South America ( n = 364), the United States ( n = 275) and the United Kingdom ( n = 85). Survival was estimated using Kaplan–Meier methods. Acute ATL was more frequent in Japan (59%) than in the United States (45%), South America (36%) and the United Kingdom (24%) ( p _{heterogeneity} < 0.0001). Conversely, lymphomatous ATL predominated in the United Kingdom (53%), South America (51%) and the United States (45%) relative to Japan (20%) ( p _{heterogeneity} < 0.0001). With a median follow‐up of 38 months interquartile range (IQR 14–68), 3‐year OS across regions ranged from 10% to 25% for acute, 16%–34% for lymphomatous, 49%–86% for chronic and 60%–83% for smouldering ATL. Evidence of regional differences in OS was observed for acute, lymphomatous and chronic ATL but not for smouldering ATL. In conclusion, the distribution of ATL subtypes varies globally, and OS for aggressive subtypes (i.e. acute and aggressive) remains poor across regions. Our findings could guide the design of clinical studies aimed at developing accessible therapies through international collaboration.

Adult T‐cell leukemia‐lymphoma (ATL) is a rare, aggressive malignancy prevalent in Japan, the Caribbean, and Central/South America. This multicenter retrospective study evaluated the effectiveness and safety of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisolone (BV‐CHP) in patients aged ≥ 18 years with previously untreated CD30‐positive ATL, verified through immunohistochemistry/flow cytometry, from six hospitals in Japan. Outcomes included overall response rate (ORR; primary outcome), overall survival (OS), progression‐free survival (PFS), complete response rate (CRR), disease control rate (DCR), and safety. Subgroup analyses evaluated lesion site, ATL subtype, age, and CD30 expression. Of 46 screened patients, 36 (median age 71 years; 66.7% female) were analyzed and started BV‐CHP between April 2020 and January 2024. CD30 positivity was confirmed in all patients. ORR was 86.1% (95% confidence interval [CI] 70.5–95.3), CRR 61.1% (95% CI 43.5–76.9), and DCR 91.7% (95% CI 77.5–98.3). ORR by lesion site (lymph nodes, peripheral blood, skin) was 93.8%, 90.9%, and 83.3%, respectively, by ATL subtype (acute, lymphoma) was 78.9% and 94.1%, respectively, and by age (≤ 70 years, > 70 years) was 84.6% and 87.0%, respectively. One patient with CD30 expression < 10% achieved a complete response; ORR was 73.7% in 19 patients with CD30 expression ≥ 10%. Median OS and PFS was 535 days (95% CI 343–not estimable) and 205 days (95% CI 166–279), respectively. Treatment‐emergent adverse events of any grade and grade ≥ 3 both occurred in 88.9% of patients, with neutropenia, febrile neutropenia, and thrombocytopenia being most common. Among 11 patients who underwent allogeneic stem cell transplantation, two developed acute graft‐versus‐host disease; median PFS was 234 days (95% CI 168–343), compared with 180 days (95% CI 96–279) without transplantation. BV‐CHP demonstrated high ORR and CRR across age groups and ATL subtypes with a manageable safety profile, supporting its potential use as a standard treatment option.

Retroviruses integrate their genetic material into the host genome, enabling persistent infection. Human T cell leukaemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1) share similarities in genome structure and target cells, yet their infection dynamics differ drastically. While HIV-1 leads to high viral replication and immune system collapse, HTLV-1 establishes latency, promoting the survival of infected cells and, in some cases, leading to leukaemia. The mechanisms underlying this latency preference remain unclear. Here we analyse blood samples from people with HTLV-1 and identify an open chromatin region within the HTLV-1 provirus that functions as a transcriptional silencer and regulates transcriptional burst. The host transcription factor RUNX1 binds to this open chromatin region, repressing viral expression. Mutation of this silencer enhances HTLV-1 replication and immunogenicity, while its insertion into HIV-1 suppresses viral production. These findings reveal a strategy by which HTLV-1 ensures long-term persistence, offering potential insights into retroviral evolution and therapeutic targets.

Here, we report a rare case of relapsed adult T-cell leukemia-lymphoma (ATL) with evidence of clonal relapse 26 years after initial diagnosis. The patient had been diagnosed with an aggressive form of lymphoma-type ATL 26 years prior and did not receive further ATL treatment for approximately 26 years after achieving complete remission. We used nested PCR to identify the amplification of ATL clone-specific accumulation sites in DNA from hematoxylin and eosin-stained specimens from the patient. Furthermore, the sequence of amplicons obtained from peripheral blood mononuclear cells and lymphoma cells from the previously diagnosed ATL were identical, indicating that a human T-cell leukemia virus-type 1 (HTLV-1)-infected clone identical to the one that recently caused ATL was present in the original lymphoma tissue. Although we were unable to identify this clone as the cause of the previous ATL, the peripheral leukemia cells revealed an ATL clone that was present in the tumor cells of a lymph node diagnosed 26 years earlier. To our knowledge, this is the first report demonstrating survival of HTLV-1-infected clones for a quarter of a century in a patient with recurrent ATL.

Retroviruses integrate viral genome DNA into the host cellular genome. The integrated proviral DNA serves as a template for the production of progeny viruses. There are many points of similarity between two human retroviruses, human T-cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1), such as viral genome size, structure and targeting host cells; however, their natural course in infected individuals is remarkably different. HTLV-1 induces latent infection even in the absence of anti-retroviral drugs but enhances survival of the infected cells, resulting in cancer development. In contrast, HIV-1 infection causes vigorous viral production and keep high viremia in the blood, resulting in acquired immune deficiency syndrome. However, it still remains largely unknown why HTLV-1 prefers such latency phenotype in contrast with HIV-1. Here we identified a previously unidentified open chromatin region (OCR) in the middle of HTLV-1 provirus. We found the region functioned as a transcriptional silencer for the HTLV-1 5’-LTR promoter and thus named the OCR as retrovirus silencer region (RSR). RUNX1, a host transcription factor, and the co-factors localizes to the RSR and plays a pivotal role in the silencer function. The mutant virus containing mutations in the RSR that impaired RUNX1 binding showed higher proviral expression, virus production, persistence, and immunogenicity than wild type virus. Further, insertion of the RSR into recombinant HIV-1 remarkably decreased proviral expression, virus production and cytopathic effect. In conclusion, this study discovered retroviral silencer region that enables a human retrovirus HTLV-1 to co-exist with human for tens of thousands of years by hijacking RUNX1, a key regulator of cell lineage specification in the host cells and by establishing reversible latency in infected individuals. These findings not only open new avenues for treatment but also suggest an evolutionary perspective, indicating how HTLV-1 may have evolved a robust latency mechanism through the RSR, contributing to its unique pathogenesis.

Human T‐cell leukemia virus type 1 (HTLV‐1) establishes chronic infection in humans and induces a T‐cell malignancy called adult T‐cell leukemia‐lymphoma (ATL) and several inflammatory diseases such as HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV‐1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV‐1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV‐1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV‐1‐infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti‐Gag proteins to predict high risk group in HTLV‐1 carriers. Consistent with this finding, anti‐Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti‐Gag CTLs for disease control. Our findings suggest that our strategy that combines anti‐HTLV‐1 antibodies and proviral load may be useful for prediction of the development of HTLV‐1‐associated diseases.