Human Lymphotropic Virus Research Articles

Cell Culture Evaluation Hints Widely Available HIV Drugs Are Primed for Success if Repurposed for HTLV-1 Prevention.

With an estimated 10 million people infected, the deltaretrovirus human T-cell lymphotropic virus type 1 (HTLV-1) is the second most prevalent pathogenic retrovirus in humans after HIV-1. Like HIV-1, HTLV-1 overwhelmingly persists in a host via a reservoir of latently infected CD4+ T cells. Although most patients are asymptomatic, HTLV-1-associated pathologies are often debilitating and include adult T-cell leukaemia/lymphoma (ATLL), which presents in mature adulthood and is associated with poor prognosis with short overall survival despite treatment. Curiously, the strongest indicator for the development of ATLL is the acquisition of HTLV-1 through breastfeeding. There are no therapeutic or preventative regimens for HTLV-1. However, antiretrovirals (ARVs), which target the essential retrovirus enzymes, have been developed for and transformed HIV therapy. As the architectures of retroviral enzyme active sites are highly conserved, some HIV-specific compounds are active against HTLV-1. Here, we expand on our work, which showed that integrase strand transfer inhibitors (INSTIs) and some nucleoside reverse transcriptase inhibitors (NRTIs) block HTLV-1 transmission in cell culture. Specifically, we find that dolutegravir, the INSTI currently recommended as the basis of all new combination antiretroviral therapy prescriptions, and the latest prodrug formula of the NRTI tenofovir, tenofovir alafenamide, also potently inhibit HTLV-1 infection. Our results, if replicated in a clinical setting, could see transmission rates of HTLV-1 and future caseloads of HTLV-1-associated pathologies like ATLL dramatically cut via the simple repurposing of already widely available HIV pills in HTLV-1 endemic areas. Considering our findings with the old medical saying "it is better to prevent than cure", we highly recommend the inclusion of INSTIs and tenofovir prodrugs in upcoming HTLV-1 clinical trials as potential prophylactics.

The Potential Effects and Mechanisms of Rhododendron molle Against Rheumatoid Arthritis Based on Network Pharmacology and Molecular Docking

Background: Rheumatoid arthritis (RA) is a self-inflammatory disease with increasing global morbidity and high disability. The Chinese herbal medicine Rhododendron molle G. Dons has been conventionally used to control RA without side effects for hundreds of years, but its effect and mechanism for anti-RA are still unclear. Objective: The objective of this study is to study the potential effect and mechanism of R. molle against RA from the perspective of action targets and molecular pathways. Methods: In this study, systemic network pharmacology was used to explore the potential effect and mechanisms of R. molle against RA, including drug active components collection, target prediction, PPI network construction, and GO and KEGG pathway enrichment analyses. At last, molecular docking was carried out to estimate the pharmacological effects and mechanisms. Results: A total of 19 drug-active compounds from R. molle and 188 potential therapeutic targets for RA were screened. According to the results of molecular docking, the interaction between 4 key active compounds (rhodojaponin VI, quercetin, kaempferol, rhodojaponin VI) and 10 core target proteins (TNF, AKT1, ALB, IL-1β, TP53, EGFR, CASP3, MMP9, PTGS2, BCL2) is the closest. The results of enrichment analysis showed that the most enriched pathways were pathways related to inflammation, human T-cell leukemia virus type I infection, PI3K-Akt and IL-17. Conclusion: The Chinese herbal medicine R. molle may regulate multiple pathways by interacting with multiple drug-active compounds and core targets, and cause the patient's immune system to respond accordingly, reducing the release of inflammatory factors, and relieving joint pain.

Flow cytometric profiles with CD7 and CADM1 in CD4+ T cells are promising indicators for prognosis of aggressive ATL

AbstractAdult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)–infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1–uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1–infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7–) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1–infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.

Novel paired CD13-negative (MT-50.1) and CD13-positive (MT-50.4) HTLV-1-infected T-cell lines with differential regulatory T cell-like activity

Adult T-cell leukemia/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4+CD25+ phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13+ Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13− (designated as MT-50.1) and CD13+ (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-β, expressed higher levels of Foxp3, and showed stronger suppression of CD4+CD25− T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13+Foxp3+ HTLV-1-infected cells.

Ag/AgCl‐Like Photogating of a COF‐on‐MOF Heterojunction in Organic Photoelectrochemical Transistor

AbstractThe pursuit of high on‐to‐off ratio (IOn/IOff), as one of the important performances for organic electrochemical transistor (OECT) has been ongoing, but to date, limited solutions are available. The interaction between light and matter has been demonstrated as a rich source for advanced electronic applications. However, its potential in IOn/IOff modulation has not been fully explored. Herein, the challenge is addressed through the unique light‐material interplay, which is represented by organic photoelectrochemical transistor (OPECT) gated by photosensitive COF‐LZU1 on mixed‐ligand MOF (COF‐on‐MOF) upon appropriate exposure illumination. Notably, the interplay between light and COF‐on‐MOF can adjust the device physics, optimizing the IOn/IOff to its maximum and enhancing signal transduction. Toward bio‐application, via exonuclease‐assisted cyclic cleavage amplification and hybridization chain reaction, such a device is validated for highly sensitive detection capabilities for human T‐cell lymphotropic virus type II (HTLV‐II) DNA down to 0.003 fM. This study features the possibility of Ag/AgCl‐like photogating of organic transistors via light‐matter interplay.

Role of the CTCF Binding Site in Human T-Cell Leukemia Virus-1 Pathogenesis.

During HTLV-1 infection, the virus integrates into the host cell genome as a provirus with a single CCCTC binding protein (CTCF) binding site (vCTCF-BS), which acts as an insulator between transcriptionally active and inactive regions. Previous studies have shown that the vCTCF-BS is important for maintenance of chromatin structure, regulation of viral expression, and DNA and histone methylation. Here, we show that the vCTCF-BS also regulates viral infection and pathogenesis in vivo in a humanized (Hu) mouse model of adult T-cell leukemia/lymphoma. Three cell lines were used to initiate infection of the Hu-mice, i) HTLV-1-WT which carries an intact HTLV-1 provirus genome, ii) HTLV-1-CTCF, which contains a provirus with a mutated vCTCF-BS which abolishes CTCF binding, and a stop codon immediate upstream of the mutated vCTCF-BS which deletes the last 23 amino acids of p12, and iii) HTLV-1-p12stop that contains the intact vCTCF-BS, but retains the same stop codon in p12 as in the HTLV-1-CTCF cell line. Hu-mice were infected with mitomycin treated or irradiated HTLV-1 producing cell lines. There was a delay in pathogenicity when Hu-mice were infected with the CTCF virus compared to mice infected with either p12 stop or WT virus. Proviral load (PVL), spleen weights, and CD4 T cell counts were significantly lower in HTLV-1-CTCF infected mice compared to HTLV-1-p12stop infected mice. Furthermore, we found a direct correlation between the PVL in peripheral blood and death of HTLV-1-CTCF infected mice. In cell lines, we found that the vCTCF-BS regulates Tax expression in a time-dependent manner. The scRNAseq analysis of splenocytes from infected mice suggests that the vCTCF-BS plays an important role in activation and expansion of T lymphocytes in vivo. Overall, these findings indicate that the vCTCF-BS regulates Tax expression, proviral load, and HTLV pathogenicity in vivo.

Trans-Activation of the Coactivator-Associated Arginine Methyltransferase 1 (Carm1) Gene by the Oncogene Product Tax of Human T-Cell Leukemia Virus Type 1.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma. The oncogene product Tax of HTLV-I is thought to play crucial roles in leukemogenesis by promoting proliferation of the virus-infected cells through activation of growth-promoting genes. These genes code for growth factors and their receptors, cytokines, cell adhesion molecules, growth signal transducers, transcription factors and cell cycle regulators. We show here that Tax activates the gene coding for coactivator-associated arginine methyltransferase 1 (CARM1), which epigenetically enhances gene expression through methylation of histones. Tax activated the Carm1 gene and increased protein expression, not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs). Tax increased R17-methylated histone H3 on the target gene IL-2Rα, concomitant with increased expression of CARM1. Short hairpin RNA (shRNA)-mediated knockdown of CARM1 decreased Tax-mediated induction of IL-2Rα and Cyclin D2 gene expression, reduced E2F activation and inhibited cell cycle progression. Tax acted via response elements in intron 1 of the Carm1 gene, through the NF-κB pathway. These results suggest that Tax-mediated activation of the Carm1 gene contributes to leukemogenic target-gene expression and cell cycle progression, identifying the first epigenetic target gene for Tax-mediated trans-activation in cell growth promotion.

Clinical Features and Survival Outcome in Aggressive-Type Adult T-Cell Leukemia/Lymphoma Patients: Real-Life Experience of a Single Center from an HTLV-1 Endemic Country.

Background and Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell lymphoproliferative disease associated with the human T-cell lymphotropic virus type I (HTLV-1). ATLL is a rare disease, found more frequently in HTLV-1-endemic areas, Romania being one of them. Despite treatment advances, the prognosis remains dismal. We aimed to describe the clinical, biological, and survival outcome features of Romanian patients with aggressive-type ATLL. Materials and Methods: We report the data of a prospective, observational, and unicentric study of all 20 patients diagnosed with lymphoma and acute types of ATLL at our center over the past 12 years. Data were collected from the patients' medical records. Results: Lymphoma-type ATLL (60%) was more common than acute-type ATLL (40%). Median age at diagnosis was 40.5 years, and most patients were female. Laboratory data revealed significant differences between acute and lymphoma-type ATLL, namely, higher leukocyte (p = 0.02) and lymphocyte counts (p = 0.02) and higher levels of corrected calcium (p = 0.001) in acute-type ATLL. All patients received chemotherapy, and only two underwent allogeneic stem cell transplantation. Only six patients obtained a complete or partial response to chemotherapy, mostly the lymphoma-type ones. The median survival for all patients was 6.37 months, with higher survival in the lymphoma-type ATLL (8.16 months) than in the acute-type (3.60 months). Normal calcium levels (p = 0.011), uric acid (p = 0.005), BUN score (p = 0.000), JCOG-PI moderate risk (p = 0.038), and obtaining complete or partial response (p = 0.037) were associated with higher survival. Conclusion: Aggressive-type ATLL among Romanian patients presents distinct characteristics, including younger age at diagnosis, female predominance, and higher incidence of lymphoma-type ATLL compared to currently reported data. Survival remains very low, with all subtypes experiencing a median survival of less than one year.

Cellular Transformation by Human Cytomegalovirus.

Epstein-Barr virus (EBV), Kaposi sarcoma human virus (KSHV), human papillomavirus (HPV), hepatitis B and C viruses (HBV, HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV) are the seven human oncoviruses reported so far. While traditionally viewed as a benign virus causing mild symptoms in healthy individuals, human cytomegalovirus (HCMV) has been recently implicated in the pathogenesis of various cancers, spanning a wide range of tissue types and malignancies. This perspective article defines the biological criteria that characterize the oncogenic role of HCMV and based on new findings underlines a critical role for HCMV in cellular transformation and modeling the tumor microenvironment as already reported for the other human oncoviruses.

Epidemiological and clinical profile of HTLV-1 patients: a closer look at a reference center in Bahia, Brazil.

The human T-lymphotropic virus type 1 (HTLV-1) affects over 5 million people worldwide and is endemic in Brazil. Though HTLV-1 is a notifiable disease, the last epidemiological report regarding HTLV-1 infection covered the period from 2012 to 2019. To understand the specific challenges and to develop the best strategies for controlling HTLV-1 infection, it is important to know the characteristics of each region providing care to people living with this virus. This descriptive cross-sectional study evaluated patients treated at the HTLV reference center in Vitória da Conquista, Bahia, Brazil, between July 2021 and August 2022. The data were obtained through the analysis of medical records and routine clinical consultations. A total of 67 patients were evaluated, with 79.1% being female, 79.1% identifying as black, indigenous, and people of color, 37.31% being married, 80.6% identifying as heterosexual, and 59.7% reporting inconsistent condom use. Additionally, 37.3% of the patients were diagnosed with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic disease with a considerable effect on the quality of life. Furthermore, 53.7% of the patients had incomplete/complete elementary education, and 52.2% had an income of up to one minimum wage. The data highlight the necessity for more specific public policies (such as health education strategies, aimed at reducing the number of new infections) targeting the described at-risk population.

Human T-cell lymphotropic virus type 1 (HTLV-1) grip on T-cells: investigating the viral tapestry of activation

IntroductionHuman T-cell Lymphotropic virus type 1 (HTLV-1) belongs to retroviridae which is connected to two major diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and Adult T-cell leukemia/lymphoma (ATLL). This study aims to investigate the mRNA expressions of key proteins correlated to T-cell activation in asymptomatic carriers (ACs) HTLV-1 infected patients, shedding light on early molecular events and T-cell activation following HTLV-1 infection.Material and MethodsThe study involved 40 participants, including 20 ACs and 20 healthy subjects. Blood samples were collected, ELISA assessment for screening and confirmation with PCR for Trans-activating transcriptional regulatory protein (Tax) and HTLV-1 basic leucine zipper factor (HBZ) of the HTLV-1 were done. mRNA expressions of C-terminal Src kinase (CSK), Glycogen Synthase Kinase-3 Beta (GSK3β), Mitogen-Activated Protein Kinase 14 (MAP3K14 or NIK), Phospholipase C Gamma-1 (PLCG1), Protein Tyrosine Phosphatase non-Receptor Type 6 (PTPN6) and Mitogen-Activated Protein Kinase Kinase Kinase-7 (SLP-76) and Mitogen-Activated Protein Kinase14 (MAP3K7 or TAK1) were assayed using RT-qPCR. Statistical analyses were performed using PRISM and SPSS software.ResultsWhile there were no significant upregulation in CSK and PTPN6 in ACs compared to healthy individuals, expression levels of GSK3β, MAP3K14, PLCG1, SLP-76, and TAK1 were significantly higher in ACs compared to healthy subjects which directly contributes to T-cell activation in the HTLV-1 ACs.ConclusionHTLV-1 infection induces differential mRNA expressions in key proteins associated with T-cell activation. mRNAs related to T-cell activation showed significant upregulation compared to PTPN6 and CSK which contributed to T-cell regulation. Understanding these early molecular events in ACs may provide potential markers for disease progression and identify therapeutic targets for controlling viral replication and mitigating associated diseases. The study contributes novel insights to the limited literature on T-cell activation and HTLV-1 pathogenesis.

NF-κB1 deficiency promotes macrophage-derived adrenal tumors but decreases neurofibromas in HTLV-I LTR-Tax transgenic mice.

Human T-cell leukemia virus type I (HTLV-I) is an oncogenic virus whose infection can cause diverse diseases, most notably adult T-cell leukemia/lymphoma (ATL or ATLL), an aggressive and fatal malignancy of CD4 T cells. The oncogenic ability of HTLV-I is mostly attributed to the viral transcriptional transactivator Tax. Tax alone is sufficient to induce specific tumors in mice depending on the promotor used to drive Tax expression, thereby being used to understand HTLV-I tumorigenesis and model the tumor types developed in Tax transgenic mice. Tax exerts its oncogenic role predominantly by activating the cellular transcription factor NF-κB. Here, we report that genetic deletion of NF-κB1, the prototypic member of the NF-κB family, promotes adrenal medullary tumors but suppresses neurofibromas in mice with transgenic Tax driven by the HTLV-I Long Terminal Repeat (LTR) promoter. The adrenal tumors are derived from macrophages. Neoplastic macrophages also infiltrate the spleen and lymph nodes, causing splenomegaly and lymphadenopathy in mice. Nevertheless, the findings could be human relevant, because macrophages are important target cells of HTLV-I infection and serve as a virus reservoir in vivo. Moreover, the spleen, lymph nodes and adrenal glands are the most common sites of tumor cell infiltration in HTLV-I-infected patients. These data provide new mechanistic insights into the complex interaction between Tax and NF-κB, therefore improving our understanding of HTLV-I oncogenic pathogenesis. They also expand our knowledge and establish a new animal model of macrophage neoplasms and adrenal tumors.

Anticancer potential of isovanillin-based symmetrical azine: Synthesis, structure, molecular modeling, in silico leukemia inhibition and MD simulation

Isovanillin azine, a symmetrical azine easily synthesized by reaction of 3-hydroxy-4-methoxybenzaldehyde (isovanillin) with hydrazine hydrate, was identified as a potential inhibitor of the Human T-cell Leukemia Virus type 1 (HTLV-1) protease (2B7F). The compound was characterized using FT-IR, UV-VIS, 1H NMR, and 13C NMR spectroscopic techniques, as well as by single-crystal X-ray diffraction at 100 K. Additionally, calculations were conducted on the FMOs, particularly the HOMO-LUMO, to determine the forbidden energy gap and assess the compound's properties. To properly and accurately evaluate the effectiveness of our product as an anticancer drug, we investigated its interactions with 2B7F through molecular docking experiment and MD simulation. The results indicate that isovanillin azine has the potential to effectively inhibit 2B7F, laying the groundwork for the development of targeted treatments for HTLV-1-related disorders.

Profile of Nagasaki Islands Study (NaIS): A Population-based Prospective Cohort Study on Multi-disease.

In an aging society, it is important to visualize the conditions of people living with diseases or disabilities, such as frailty and sarcopenia, and determine the environmental and genetic factors underlying such conditions. Atherosclerosis and arterial stiffness are key conditions between these factors and noncommunicable diseases. In 2014, we launched a population-based prospective open-cohort study, the Nagasaki Islands Study (NaIS), which was conducted in Goto City, located in the remote islands of Nagasaki Prefecture, Japan, mostly involving middle-aged and older residents. We conducted our own health checkups along with the annual standardized checkups organized by the municipality; recruited study participants; and started to follow them for vital status (death), migration, and occurrence of diseases, such as myocardial infarction, stroke, fracture, and human T-cell leukemia virus type 1 (HTLV-1)-associated uveitis. Our checkups were conducted as baseline surveys in different areas of Goto City during the fiscal years 2014-2016, secondary surveys during 2017-2019, and tertiary surveys since 2021, consisting of medical interviews, physical examinations, blood and urine tests, body composition measurements, osteoporosis screening, arterial stiffness measurements, carotid ultrasonography, and dental examination. A total of 4,957 residents participated in either the baseline or secondary surveys and were followed; 3,594 and 3,364 residents (aged 27-96 and 28-98 years) participated in the baseline and secondary surveys, respectively. In conclusion, the NaIS has been undertaken to reveal the influence of aging and risk factors of noncommunicable diseases and disabilities, with an aim to contribute towards better healthcare in the future.

Period prevalence of uveitis in human T-lymphotropic virus 1carriers versus noncarriers in a highly endemic area: The Nagasaki Islands Study.

The magnitude of the effect of human T-lymphotropic virus 1 (HTLV-1) infection on uveitis remains unclear. We conducted a cross-sectional study in a highly endemic area of HTLV-1 in Japan. The study included 4265 residents (men, 39.2%), mostly middle-aged and older individuals with a mean age of 69.9 years, who participated in our surveys between April 2016 and September 2022. We identified HTLV-1 carriers by screening using chemiluminescent enzyme immunoassays and confirmatory tests, and the proportion of carriers was 16.1%. Participants with uveitis were determined from the medical records of all hospitals and clinics where certified ophthalmologists practiced. We conducted logistic regression analyses in an age- and sex-adjusted model to compute the odds ratio (OR) and 95% confidence interval (CI) of uveitis according to HTLV-1 infection status. Thirty-two (0.8%) participants had uveitis. For HTLV-1 carriers, the age- and sex-adjusted OR (95% CI) of uveitis was 3.27 (1.57-6.72) compared with noncarriers. In conclusion, HTLV-1 infection was associated with a higher risk of uveitis among mostly middle-aged and older Japanese residents in a highly endemic HTLV-1 area. Our findings suggest that physicians who treat HTLV-1 carriers should assess ocular symptoms, and those who diagnose patients with uveitis should consider HTLV-1 infection.

Impact and economic analysis of human T-cell lymphotropic virus type 1 (HTLV-1)-targeted antenatal screening, England and Wales, 2021.

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) is a neglected virus that can cause severe disease and be transmitted from mother to child through breastfeeding. Avoidance of breastfeeding prevents 80% of vertical transmission. The United Kingdom (UK) is currently assessing whether HTLV-1-targeted antenatal screening should be implemented.AimWe aimed to assess the impact and cost-effectiveness of a targeted programme to prevent HTLV-1 vertical transmission in England and Wales.MethodsWe estimated the number of pregnant women who have high risk of HTLV-1 infection based on their or their partner's country of birth. With data from 2021, we used a mathematical model to assess cost-effectiveness of HTLV-1 antenatal screening. We also estimated the annual number of infant infections and the number that could be prevented with screening and intervention.ResultsWe estimate that ca 99,000 pregnant women in England and Wales have high risk of HTLV-1 infection. In the absence of screening, 74 (range: 25-211) HTLV-1 infections in infants would be expected to occur every year in England and Wales. Implementation of targeted screening would prevent 58 (range: 19-164) infant infections annually. The intervention is effective (incremental 0.00333 quality-adjusted life years (QALY)) and cost-saving (GBP -57.56 (EUR -66.85)).ConclusionOur findings support implementation of HTLV-1 targeted antenatal screening to reduce vertical transmission from mothers to infants in the UK.

Lived Experience of Human T-cell Leukemia Virus type-1 -Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): A Phenomenology Study.

Human T-cell Leukemia Virus type-1 (HTLV-1) -associated myelopathy causes sufferers to experience changes in several aspects of their lives. Gaining a deeper understanding of these changes can help healthcare professionals improve care, enhance strategic decision-making, meet expectations, and manage patients effectively. However, there is no information about the experience and problems of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis in Iran. Therefore, this study aimed to explain the lived experience of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. This qualitative study used hermeneutic phenomenology in 2022 in Mashhad, Iran. Participants were selected using purposeful sampling. Data were collected through 21 semi-structured in-depth interviews with 20 eligible patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. The data were analyzed in MAXQDA/2020 using the six stages proposed by Van Manen. The main concept of "Reduced self-sufficiency and social dignity" emerged from the narratives of the patients, which included three main categories "Disruption of desirable personal and social life", "reduced perception of role competencies", and "obligatory unpleasant lifestyle changes". HTLV-1-associated myelopathy/tropical spastic paraparesis slowly makes patients feel insufficient and causes a sense of degradation in dignity. The disease can fundamentally change personal and social life. Thus, due to its incurability and progressiveness, palliative care should be provided to them to live with dignity.

Human T-cell leukemia virus type 1 uses a specific tRNAPro isodecoder to prime reverse transcription.

Human T-cell leukemia virus type 1 (HTLV-1) is the only oncogenic human retrovirus discovered to date. All retroviruses are believed to use a host cell tRNA to prime reverse transcription (RT). In HTLV-1, the primer-binding site (PBS) in the genomic RNA is complementary to the 3' 18 nucleotides (nt) of human tRNAPro The human genome encodes 20 cytoplasmic tRNAPro genes representing seven isodecoders, all of which share the same 3' 18 nt sequence but vary elsewhere. Whether all tRNAPro isodecoders are used to prime RT in cells is unknown. A previous study showed that a 3' 18 nt tRNAPro-derived fragment (tRFPro) is packaged into HTLV-1 particles and can serve as an RT primer in vitro. The role of this tRNA fragment in the viral life cycle is unclear. In retroviruses, N1-methylation of the tRNA primer at position A58 (m1A) is essential for successful plus-strand transfer. Using primer-extension assays performed in chronically HTLV-1-infected cells, we found that A58 of tRNAPro is m1A-modified, implying that full-length tRNAPro is capable of facilitating successful plus-strand transfer. Analysis of HTLV-1 RT primer extension products indicated that full-length tRNAPro is likely to be the primer. To determine which tRNAPro isodecoder is used as the RT primer, we sequenced the minus-strand strong-stop RT product containing the intact tRNA primer and established that HTLV-1 primes RT using a specific tRNAPro UGG isodecoder. Further studies are required to understand how this primer is annealed to the highly structured HTLV-1 PBS and to investigate the role of tRFPro in the viral life cycle.

Neurological aspects of HTLV-1 infection: symptoms in apparently asymptomatic carriers.

Human T-lymphotropic virus type 1 (HTLV-1) is classically associated with the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although the mechanisms of this neurological disorder remain unclear. In addition, some patients who develop "minor" neurological signs that do not meet diagnostic criteria for HAM/TSP are classified as asymptomatic carriers. This study aims to demonstrate the neurological symptoms of Brazilian patients living with HTLV-1 classified as not-HAM.TSP.This observational study evaluated patients treated in an HTLV reference center in Bahia, Brazil, between February 2022 and July 2023. The data were obtained through the analysis of medical records and neurological consultation. Those individuals classified as HAM/ TSP were excluded from this study. 74 patients were submitted to a careful neurological evaluation: 23 HAM/TSP, 22 were classified with intermediate syndrome (IS), and 29 were oligosymptomatic. Self-reported symptoms were significantly more common in the IS group, including urinary symptoms such as nocturia, urgency, incontinence, dysuria, weakness, paresthesia, lumbar pain, xerostomia, and xerophthalmia. Physical examination findings consistent with reduced vibratory and tactile sensitivity were more common in the IS group (p = 0.017 and p = 0.013). Alterations in the V and VIII cranial nerves were present in both groups. HTLV-1 can lead to the development of important neurological signs and symptoms in apparently asymptomatic individuals. This data highlights the need for more research into the neurological aspects of HTLV-1 infection and emphasizes the importance of early diagnosis, treatment, and support for individuals living with this virus.

Dynamics and optimal therapy of a stochastic HTLV‐1 model incorporating Ornstein–Uhlenbeck process

As the prevalence of viral infection in body, human T‐cell leukemia virus type 1 (HTLV‐1) is receiving increasing attention. Research on the corresponding virus models is of great significance to tackle the challenges of understanding HTLV‐1 development and treatment. This paper focuses on the dynamic analysis for a stochastic model with nonlinear cytotoxic T lymphocyte (CTL) response, which is driven by Ornstein–Uhlenbeck (OU) process to model the progression of HTLV‐1 in vivo. Rich dynamic behaviors such as the extinction of infected CD4+ T cells (ITCs), stationary distribution (SD), probability density, and finite‐time stability (FTS) of the model are established to reveal the interaction of cell populations. The optimal therapeutic strategy based on the cost‐benefit viewpoint is further obtained. Finally, illustrative numerical simulations are represented to corroborate the effectiveness of treatment and the ambient perturbation's impact that strengthening the noise strength can lead to rapid virus clearance.