HTLV-1関連脊髄症

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit IKBKG/NEMO and directly engages the ubiquitin-dependent PINK1-PRKN/parkin pathway to induce mitophagy. Tax also recruits autophagy receptors CALCOCO2/NDP52 and SQSTM1/p62 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires PRKN to limit the extent of CGAS-STING1 activation and suppress type I interferon (IFN) induction. HTLV-1-transformed T-cell lines and PBMCs from HAM/TSP patients exhibit hallmarks of chronic mitophagy, and inhibition of PRKN in HTLV-1-transformed cell lines downregulates p19 Gag expression and induces cell death. Collectively, our findings suggest that Tax manipulation of the PINK1-PRKN mitophagy pathway represents a new HTLV-1 immune evasion strategy important for maintaining viral gene expression and cell survival.

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.

An 84-year-old woman presented with a two months history of progressive bilateral lower limb weakness and bladder bowel disfunction. Neurological examination revealed spastic paraplegia and anti HTLV-1 antibodies were positive in the serum and cerebrospinal fluid. Due to the rapid progression along with the elevation of neopterin and CXCL-10 in the cerebrospinal fluid, the diagnosis of rapidly progressive HTLV-1 associated myelopathy (HAM) was made. Chest X-ray and CT coincidentally revealed diffuse micronodular opacities, nodular in various sizes, and interlobular septal thickening. HTLV-1 associated bronchioalveolar disorder was the most likely diagnosis. Steroid therapy was effective against both spastic paraplegia and pulmonary lesions. Although the pulmonary lesions were identified incidentally in our case, screening for pulmonary lesions is important in patients with spastic paraplegia as it may lead to early diagnosis of HAM.

Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with a broad spectrum of neurological manifestations, including conditions that may precede the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This analytical, descriptive cross-sectional study aimed to estimate the prevalence of HTLV-1 infection and describe associated sociodemographic, socioeconomic, behavioral, and clinical characteristics among patients with neurological disorders followed at a tertiary public hospital in Northeast Brazil between 2024 and 2025. A total of 300 patients underwent serological screening using an enzyme-linked immunosorbent assay (ELISA) with a commercial kit (DiaSorin Murex HTLV-1 + 2). Samples with positive or indeterminate results underwent DNA extraction and molecular confirmation by polymerase chain reaction (PCR) to differentiate viral types. Three patients tested positive for HTLV-1, resulting in an overall prevalence of 1.0%. All HTLV-1-positive individuals were women aged 43 to 72 years with low educational attainment and income. Univariate analyses identified significant associations with injection drug use, history of blood transfusion, and family history of HTLV-1 infection. Clinically, HTLV-1-positive patients presented heterogeneous neurological manifestations, ranging from urinary dysfunction and lower limb sensory and motor impairment to musculoskeletal and inflammatory symptoms. These findings highlight the broad spectrum of neurological involvement associated with HTLV-1 infection. Early identification of HTLV-1 may contribute to improved clinical management and inform public health strategies.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) infection is usually asymptomatic; however, around 3% of infected individuals develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Host genetic variants of innate immunity may contribute to this clinical outcome. OBJECTIVE: To investigate the association between MBL2 polymorphisms and HAM/TSP in people living with HTLV-1. METHODS: This case-control study included 89 individuals with confirmed HTLV-1 infection who were followed at an outpatient clinic for at least three years. Of these, 64 were asymptomatic and 25 developed HAM/TSP. Polymorphisms in the MBL2 promoter regions -550 (H/L; rs.11003125) and -221 (Y/X; rs.7096206), and in exon 1 (A/O; rs.5030737, rs.1800450, and rs.1800451) were genotyped. Combined haplotypes were classified according to previously described genotype-based functional categories related to high/intermediate or low/deficient MBL production. Serum MBL levels were not directly measured. RESULTS: The H allele and HH/HL genotypes at -550 were more frequent in asymptomatic individuals than in patients with HAM/TSP. In the combined analysis, low/deficient predicted MBL producers were more frequent in the HAM/TSP group than in the asymptomatic group (48 vs. 23%; OR 3.02, 95% CI 1.01-8.89; p = 0.02). CONCLUSION: MBL2 polymorphisms were associated with HAM/TSP status in this cohort. However, these findings should be interpreted cautiously due to the small sample size, the absence of proviral load data for most participants, and the lack of direct serum MBL measurements. Larger independent studies are needed to confirm these associations.