Search Results (341)

The proviral load of human T-cell lymphotropic virus type 1 (HTLV-1) is an important biomarker associated with the monitoring and risk stratification of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the lack of standardized quantification methods limits its broader application. This study evaluated a novel absolute quantification approach based on whole blood volume and compared its performance with established protocols. A total of 66 HTLV-1-infected individuals were analyzed using six qPCR-based methodologies, including volumetric quantification (copies/µL) by absolute quantification and the Tamegão-Lopes method, as well as normalization per 1000 cells (whole blood, buffy coat, PBMCs, and CD4+ T cells). Association and agreement were assessed using Pearson’s correlation, Bland–Altman analysis, concordance correlation coefficients (CCCs), and Deming regression. Absolute quantification showed strong correlation with both the Tamegão-Lopes method and CD4+-based quantification (r = 0.93 and 0.84, respectively; p < 0.001) and high agreement (CCC = 0.866 and 0.811, respectively), with modest systematic bias (−0.273 log₁₀ copies/µL and 0.115 log₁₀ copies/10³ cells, respectively). Leukocyte-normalized methods showed greater discrepancies, likely due to dilution by uninfected cells. These findings show that quantification based on total blood volume is a simplified, operationally feasible alternative for assessing HTLV-1 proviral load. Full article

Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease of the spinal cord induced by immunological activation due to high HTLV-1 proviral load in the peripheral blood. HAM/TSP is representative of HTLV-1-related inflammatory diseases, and its main neurological symptoms—namely, motor dysfunction of the lower extremities through spastic paraparesis with urinary disturbance—are progressive and lead to deterioration in the quality of life of patients once these dysfunctions develop. Therefore, novel and safe therapeutic regimens are needed, enabling patients to commence treatment as soon as possible after the diagnosis of HAM/TSP. To date, various treatments have been developed for the correction of the associated immunological or virological abnormalities, which have produced some good results. However, there are still many problems, such as insufficient treatment effects and side effects. In addition, most of these treatments have only been characterized in the short term, being in the open trial phase, and it remains unclear whether or not they are suitable for the long-term treatment of HAM/TSP induced by a chronic inflammatory status. Thus, we need effective therapeutic regimens with safety for long-term or even lifelong courses of treatment. In this review, we summarize the clinical trials conducted to date for various therapeutic approaches, including representative regimens against HAM/TSP, while touching on the problematic issues. In addition, we discuss several agents with the potential to enable the development of novel therapeutic regimens as emerging interventions for further investigation in future research. Full article

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory disease driven by HTLV-1-infected CD4⁺ T cells; however, the phenotypic and functional characteristics of disease-associated T-cell subsets remain incompletely understood. We analyzed samples using flow cytometry (n = 3–5 per group) and RNA-seq (n = 13), focusing on CADM1^highCD4⁺ T cells enriched for HTLV-1-infected cells to evaluate a transferrin receptor (TfR)-expressing subset. TfR⁺CADM1^highCD4⁺ T cells were detected in both asymptomatic carriers and patients with HAM, but their frequency among CD4⁺ T cells was higher in HAM patients. These cells exhibited a Treg-like phenotype with higher Foxp3 and CTLA-4 expression than TfR⁻ cells and showed increased Ki-67 positivity, consistent with proliferation. Despite this phenotype, they produced interferon-γ, indicating inflammatory potential, while Foxp3 expression was lower in HAM patients than in asymptomatic carriers, suggesting a more inflammatory phenotype. Furthermore, TfR transcript levels (RNA-seq TPM) correlated with clinical indicators of disease activity, including neopterin and CXCL10 protein levels, and the Osame motor disability score. Collectively, these findings suggest that TfR identifies a proliferative, Foxp3-low, Treg-like inflammatory CD4⁺ T-cell subset that is associated with disease activity in HAM. Full article

Coinfection between hepatitis C virus (HCV) and human T-lymphotropic virus 1/2 (HTLV-1/2) remains poorly investigated in the Northern Region of Brazil despite its clinically important condition. The objective of this study was to determine the prevalence and describe the epidemiological and behavioral risk factors for HCV/HTLV-1/2 coinfection in Belém, Pará. This observational, descriptive, and cross-sectional study analyzed 192 samples from patients previously diagnosed with HCV: 127 participants recruited between May 2023 and June 2025 and 65 samples previously stored in the Virology Laboratory of UFPA. Data were collected through a structured survey. Serological screening for HTLV-1/2 was performed by enzyme-linked immunosorbent assay (ELISA) and confirmed by INNO-LIA and molecular biology (qPCR). HCV/HTLV-1/2 coinfection was observed in 4 individuals (2.1%), of whom 1.6% had HCV/HTLV-1 coinfection and 0.5% HCV/HTLV-2. There was no statistically significant association when comparing the sociodemographic, clinical characteristics, or risk factors of HCV monoinfected and HCV/HTLV-1/2 coinfected individuals. Although the results show a low prevalence of HTLV-1/2 and HCV coinfection in Belém do Pará, they still reinforce the importance of including HTLV in testing protocols for patients with hepatitis C in the North region of Brazil. Full article

Human T-cell leukemia virus type-1 (HTLV-1) is endemic to numerous regions worldwide, including Central Australia. The Australo-Melanesian subtype-C is endemic within Australia and Oceania, whereas subtype-A is the most widely distributed subtype globally. The lack of an approved vaccine highlights HTLV-1 as a neglected public health issue. To inform the development of HTLV-1 Envelope (Env)-based vaccines, we assessed anti-Env antibodies in an HTLV-1c+ cohort of First Nations individuals in Central Australia. Of the 62 plasma samples from patients with confirmed HTLV-1 serological diagnosis, 76% were positive for Env binding in ELISA, but 90% neutralized HTLV-1c pseudovirus (PSV) infection. Neutralization breadth with the capability of blocking both subtype-A and subtype-C PSV infection was identified in 100% of samples tested. Proviral load was positively associated with anti-Env response, with binding epitopes mapping to the proline-rich region of gp46-SU. Env-directed IgG showed the capacity to engage Fcγ receptors key to inducing antibody-dependent cellular cytotoxicity/phagocytosis responses. Serological response was not associated with comorbidities linked to HTLV-1c in this population (bronchiectasis, chronic kidney disease, diabetes). These findings demonstrate that potent humoral immunity arises and is sustained during HTLV-1 infection, suggesting that an Env-based vaccine displaying authentically native epitopes will be capable of recapitulating these neutralizing responses. Full article

HTLV-1 and HTLV-2 infections are associated with various neurological manifestations, particularly HTLV-1-associated myelopathy (HAM). This descriptive, cross-sectional observational study aimed to investigate and analyze the neurological manifestations in patients treated at the Service for the Care of People Living with HTLV (Serviço de Atendimento à Pessoa Vivendo com HTLV-SAPEVH) at the Federal University of Pará. A cohort of 957 individuals underwent screening for HTLV-1/2 infection using enzyme-linked immunosorbent assay (ELISA), with seropositive samples subsequently confirmed via Western blotting or quantitative polymerase chain reaction (qPCR). HTLV-1/2 infection was confirmed in 69 individuals. Of these, fifteen individuals—diagnosed with HTLV-1 (n = 11) or HTLV-2 (n = 4) infection—who presented with neurological complaints at the first nursing consultation, were referred to a neurologist for clinical evaluation of neurological signs and symptoms. Most of the patients were female (13), ranging from 33 to 80 years of age. Neurological symptoms were present in 86.7%, and included spasticity, paraparesis, chronic pain, both motor and sensory deficits, as well as urinary disorders, predominantly affecting the thoracic spinal cord and lower limbs. Urinary symptoms were observed in 77% of symptomatic patients, often preceding other neurological signs that suggest a role as “sentinel symptoms” in the clinical screening of HTLV carriers. The results demonstrated the presence of neurological impairment in patients infected with both HTLV-1 and HTLV-2, with motor symptoms ranging from moderate to advanced. In addition, cases of cranial nerve and upper limb involvement were reported, a finding that is rarely described in the literature. The study highlights the importance of neurological assessment as early as possible in patients infected with either HTLV-1 or HTLV-2 and suggests that sphincter dysfunctions can serve as early clinical markers of future neurological impairment. Full article

Co-infection with human T-cell lymphotropic virus types 1 and 2 (HTLV-1/2) and HIV is not routinely screened for, yet it may significantly influence clinical progression, mortality, and quality of life in affected individuals. This study aimed to estimate the prevalence of HTLV-1/2 co-infection among adults living with HIV and to identify associated epidemiological factors in the Peruvian Amazon. A cross-sectional study was conducted including patients receiving antiretroviral therapy through the multidisciplinary TARGA program in Iquitos, Peru, during the second quarter of 2013. Screening for HTLV-1/2 antibodies was performed using enzyme-linked immunosorbent assay, with reactive samples confirmed by Line Immunoassay. Demographic and behavioral variables were collected, and prevalence odds ratios with 95% confidence intervals were estimated using logistic regression models. Among the 284 patients included, 28 were co-infected with HIV and HTLV-1/2, resulting in a prevalence of 10% with a 95% confidence interval of 6.5 to 14.1. In multivariable analysis, age over 35 years and having more than 10 lifetime sexual partners were independently associated with co-infection, with prevalence odds ratios of 12.4 and 3.6, respectively. HTLV-1/2 co-infection was highly prevalent among people living with HIV in the Peruvian Amazon, and the main risk factors identified suggest that cumulative exposure and sexual behavior play a significant role in the joint transmission of both retroviruses, supporting the need to consider systematic HTLV screening in endemic settings. Full article

Hepatitis B virus (HBV) and human T-lymphotropic virus type 1 (HTLV-1) are blood-borne pathogens with overlapping transmission routes, resulting in an increased prevalence of HBV among individuals infected with HTLV-1. Notwithstanding the widespread application of mathematical modeling to the study of each virus in isolation, the within-host dynamics of HBV–HTLV-1 co-infection remain insufficiently characterized. This study introduces a novel within-host co-infection model that characterizes the interactions between HBV and HTLV-1, where HTLV-1 infects CD4⁺ T cells and HBV targets hepatocytes. A comprehensive qualitative analysis yields four threshold parameters ($R_i,i=1,2,3,4$) governing the existence and stability of equilibrium points, with global stability established using Lyapunov functions. Numerical simulations validate the analytical results, and sensitivity analysis identifies parameters that most strongly influence the basic reproduction numbers for HBV ($R_1$) and HTLV-1 ($R_2$) mono-infections. Our results corroborate that, in patients with HBV, the presence of HTLV-1 contributes to an elevated HBV viral load and CD4⁺ T cells play a crucial role in controlling HBV infection. Full article

Persistent oncovirus infections account for 15–20% of the global cancer burden, driving multiple forms of human cancer. To maintain persistent infection and spread, oncoviruses drive alterations in host cell metabolism, immune signaling, and cell-to-cell communication throughout tumor microenvironments. Accumulating evidence has indicated that these alterations occur in conjunction with a range of organelle remodeling events that can differ between “dormant” viral latency and active lytic replication. Throughout each phase of infection, oncoviruses alter the morphology, composition, and function of organelles to promote cellular survival and proliferation, while periodically supporting viral replication. Here, we review oncovirus-driven organelle remodeling strategies across distinct infection states, including viral latency, reactivation from latency, and chronic active replication. We focus on the molecular mechanisms by which oncovirus-driven organelle remodeling promotes cellular transformation, impedes immune responses, and facilitates virion assembly and egress. We also draw parallels between remodeling strategies employed by oncogenic and oncomodulatory viruses, emphasizing broadly conserved mechanisms across cancer-associated infections. Lastly, we highlight how studies of oncovirus organelle remodeling are critical for discovering vulnerabilities in both oncogenic virus infection and viral oncogenesis, with therapeutic potential for multiple cancers. Full article

Human T-cell lymphotropic virus type 1 (HTLV-1) can cause HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neuroinflammatory disease that lacks noninvasive biomarkers. We used untargeted urine metabolomics with machine learning to profile 113 participants (39 with HAM, 17 with intermediate syndrome, 33 asymptomatic carriers, and 24 healthy controls). Gas chromatography–mass spectrometry identified 175 metabolites, 86 of which showed significant differences (fold change > 2, FDR p < 0.05). Multivariate analyses revealed distinct but partially overlapping metabolic profiles: sPLS-DA captured a reproducible yet moderately discriminative signal, while nonlinear machine learning models (Random Forest and SVM) achieved robust group separation, with HAM displaying a distinct metabolic signature. Key discriminators included Unknown_151, Unknown_127, histidine, alanine, and 4-hydroxyphenylacetic acid, which showed marked reductions in HAM and yielded ROC AUCs of 0.855–0.871. Pathway and disease enrichment analyses highlighted disturbances in amino acid metabolism, particularly beta-alanine and aromatic amino acids, along with disease signatures related to inherited amino acid handling disorders such as hyperlysinemia. These results demonstrate that urinary metabolomics combined with machine learning can identify potential noninvasive biomarkers for HAM and provide novel insights into HTLV-1-associated pathophysiology. Full article

HTLV-1 and HIV-1 represent biologically significant, structurally close, and equally problematic yet divergent human retroviruses. Although both infect CD4+ T cells and share similar structural elements, they differ markedly in genomic stability, transmission dynamics, clinical progression, and, most importantly, their transcriptional regulatory mechanisms. HTLV-1, an ancient virus with a limited global burden, often remains asymptomatic for decades before potentially causing ATL or HAM/TSP. Conversely, HIV-1, a relatively recent zoonotic transmission, undergoes rapid replication, exhibits high genetic diversity, and causes progressive immunodeficiency unless controlled by antiretroviral therapy (ART). At the molecular level, HTLV-1 maintains proviral latency through a balanced bidirectional transcription of regulatory genes (e.g., Tax and HBZ) that manipulate host transcription and immune evasion pathways, facilitating persistence and oncogenesis. HBZ and Tax were shown to contribute to driving the progressive acquisition of Treg-like and HLA class II phenotype in chronically activated CD4+ T-cells, promoting tolerogenic antigen presentation and immune evasion in ATL cells. This well-controlled differential expression of HTLV-1 regulatory genes is attributed to multiple intragenic virus regulatory mechanisms, which will be discussed in this review. In contrast, HIV-1 transcription is driven by a tightly regulated 5′ LTR promoter involving host factors such as NF-κB, Sp1, AP-1, and NFAT, among others, with strong influence imposed by the landscape of the provirus integration site, playing a pivotal role in latency and reactivation. The distinct regulatory circuitry of each virus suggests a key difference in their essential regulation, with HTLV-1 primarily relying on intragenic mechanisms, while HIV-1 relies more heavily on interactions with the surrounding host environment to control its expression. This difference underscores unique therapeutic challenges in managing viral latency, persistence, and pathogenesis. Full article

Among the metal-derived complexes, recently, tin derivatives have been investigated as promising anti-cancer drug candidates. Our previous study showed that the tin-based compound Bu₃SnOCOCF₃ (TBT) exerts cytotoxic activity on solid tumor cell lines. In the present study, the effects of TBT were evaluated in vitro on HTLV-1-infected human lymphocytic cell lines at different stages of viral transformation, consisting of IL-2-dependent (PB2/IL-2) and IL-2-independent (PB2/NO-IL-2) cells, generated in our laboratory by HTLV-1 in vitro infection of lymphocytes from the same donor, and the C91/PL cell line established by co-cultivation with T cells from a patient with HTLV-1-positive leukemia. TBT induced a reliable and reproducible dose-dependent inhibition of metabolic activity and viability in the HTLV-1-infected cells. The effect was cell-type-dependent, with C91/PL cells being quite resistant. An investigation into the cytotoxic effects induced by TBT in HTLV-1-infected cells and data on caspase inhibitors/caspase activation indicated that apoptotic cell death was involved, but also that the possible involvement of other forms of cell death could not be excluded. Taken together, the results show for the first time that the tin-based compound, although not devoid of a certain cytotoxicity toward uninfected cells, can induce typical and potent effects on HTLV-1-infected cells. Full article

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy caused by persistent infection with human T-cell leukemia virus type 1 (HTLV-1). ATLL remains difficult to treat despite intensive chemotherapy, antiviral therapy, and hematopoietic stem cell transplantation. The limited durability of current treatment strategies highlights the need for mechanism-based therapeutic approaches. Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that regulates transcription, RNA splicing, DNA damage responses, and immune signaling through symmetric dimethylation of histone and non-histone substrates. PRMT5 is frequently overexpressed across hematologic and solid tumors. Preclinical studies indicate that PRMT5 expression is elevated during HTLV-1-mediated T-cell transformation and that pharmacologic inhibition of PRMT5 selectively impairs the survival and transformation of infected T cells in vitro and in vivo. In this review, we highlight the current understanding of PRMT5 biology in cancer, summarize preclinical studies supporting PRMT5 as a therapeutic target in ATLL, and discuss key challenges to future clinical translation. We also discuss emerging approaches such as rational combination therapies and tumor-selective PRMT5 inhibitors as potential paths toward treatment for ATLL. Full article

Human T-lymphotropic virus type 1 (HTLV-1), the first human retrovirus identified, is linked to adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. However, its post-transcriptional regulation remains poorly understood. Here, we used Oxford Nanopore direct RNA sequencing to profile the HTLV-1 transcriptome and epitranscriptome in MT2 cells. We identified 23 transcript isoforms, encompassing canonical and novel splice variants. Polyadenylation analysis revealed a predominant poly(A) tail length of around 50–100 nucleotides with transcript-specific variations. Distinct RNA modifications, including pseudouridine, N⁶-methyladenosine, and 5-methylcytidine, were enriched near the 3′ end and varied among transcript classes, with generally lower modification ratios in viral transcripts. These findings provide a more comprehensive map of HTLV-1 RNA splicing, polyadenylation, and modifications in MT2 cells, offering new insights into viral gene regulation and pathogenic mechanisms. Full article