HTLV-1 infection causes chronic immune activation and a prolonged asymptomatic phase, but the functional features that define early disease remain unclear. We evaluated whether spontaneous proliferation (SP) and related functional immune parameters can distinguish clinical stages across the HTLV-1 spectrum. Spontaneous and mitogen-induced lymphoproliferation (PHA, anti-CD3), measured by CFSE dilution, and in vitro cell death, measured by cytometry, were assessed in 435 HTLV-1-infected individuals: asymptomatic carriers (AC, n = 303), individuals with intermediate syndrome (IS, n = 21), patients with HTLV-1-associated myelopathy (HAM, n = 94), adult T-cell leukemia/lymphoma (ATL, n = 17), and two control groups. Notably, SP levels divided the asymptomatic individuals in two subgroups: low-SP (24.5

Background Human T-lymphotropic virus type 1 (HTLV-1) infection is classically categorized as either asymptomatic or associated with HTLV-1-associated myelopathy (HAM). However, accumulating clinical evidence suggests that a proportion of individuals labeled as asymptomatic present early inflammatory and neurological manifestations that do not fulfill HAM diagnostic criteria.Research design and methods We conducted an observational study within a large, long-standing Brazilian HTLV-1 cohort. Between January 2015 and December 2025, adults previously classified as asymptomatic were systematically evaluated during follow-up at an outpatient clinic. Standardized clinical and neurological examinations were newly performed by clinicians not previously involved in their care and assessment. These findings were then integrated with neuropsychological, radiological and laboratory assessments.Results Among individuals previously considered asymptomatic, 24% fulfilled predefined criteria for an intermediate condition termed HTLV-1-associated multiple inflammatory disorder (HAMID). HAMID was associated with older age, female sex, higher proviral load, markers of chronic immune activation, subtle spinal cord abnormalities, and cognitive impairment, particularly affecting episodic memory.Conclusions HTLV-1 infection encompasses an early, biologically active inflammatory disease stage distinct from both asymptomatic infection and overt HAM. Recognition of HAMID refines the clinical spectrum of HTLV-1 infection and provides a framework for earlier diagnosis, improved risk stratification, and clinical surveillance.

Mother-to-child transmission (MTCT) is the primary route of human T-lymphotropic virus type 1 (HTLV-1) infection. Although formula feeding reduces breastfeeding-associated transmission, MTCT still occurs, implicating pregnancy or delivery as key transmission windows. In this study, placental tissues from nine HTLV-1-positive mothers were analyzed using DNA/RNAscope, revealing low HTLV-1 DNA and RNA levels and a low RNA/DNA ratio, consistent with latent infection in the placenta and potentially explaining the low MTCT rate. Elevated interferon (IFN)-β levels were observed in infected placentas compared to seronegative controls, while IFNα, IFNγ, and IFITM expression remained unchanged. Concurrently, sustained IFNβ expression in infected placentas suggests its dual roles in HTLV-1 pathogenesis: suppressing viral replication while potentially disrupting placental homeostasis through chronic inflammation. In vitro modeling using BeWo cells or primary trophoblasts cocultured with HTLV-1-infected MT-2 cells demonstrated syncytin-1-mediated viral entry, confirmed by HTLV-1 p19 detection in both trophoblasts. Of note, HTLV-1 transmission was abolished by a syncytin-1-specific fusion inhibitor HRB1, underscoring syncytin-1's essential role in cell-to-cell transmission of HTLV-1. Thus, this study identifies syncytin-1 as a therapeutic target to block vertical transmission and highlights the need to balance antiviral responses with placental integrity in HTLV-1 management.

This study investigates cerebrospinal fluid (CSF) biomarkers associated with HIV-associated neurocognitive disorders (HAND) in people with HIV (PWH) in Brazil. Among 79 HIV-positive participants and 7 negative controls, elevated levels of inflammatory cytokines and soluble CD14 (sCD14) were found. The sCD14 showed promise as a diagnostic marker, and combined with other proinflammatory markers, may improve early detection and monitoring of HAND.

Neurological manifestations associated with COVID-19 remain partially described, mainly in low- and middle-income countries where diagnostic tools are limited. To address this, we assembled medical centers in Brazil with the goal of describing neurological syndromes associated with COVID-19 during the first wave of the pandemic. From June 1st, 2020 to June 1st, 2021, non-consecutive adult patients with new onset of six neurological syndromes up to 60 days after confirmed COVID-19 were included. Data were compiled from four tertiary centers and compared with general local COVID-19 data, as well as with a previous cohort focused on vascular syndrome. 197 patients were included, presenting with vascular syndromes (81), encephalopathy (68), encephalitis (19), Guillain-Barré syndrome (13), other neuropathies (12), and myelitis (4). The incidence curve of neurocovid mirrored that of COVID-19. Neurological syndromes were present regardless of COVID-19 severity. The median time from COVID-19 to onset of neurological symptoms was 14 days, suggesting a post-infectious immune-mediated mechanism. Patients were 10 times more likely to die (χ2 (1) = 356.55, p < 0.01, OR = 10.89) and 38 times more likely to be hospitalized than other COVID-19 patients (χ2 (1) = 1167.9, p < 0.01, OR = 38.22). Those developing vascular syndromes patients were 3 times more likely to require ICU (χ2 (1) = 37.12, p < 0.01, OR = 3.78) and 4 times more likely to die (χ2 (1) = 58.808, p < 0.01, OR = 4.73) than patients with vascular syndromes due to different etiologies. Our study corroborates the association of neurological syndromes with COVID-19. The incidence correlated with local waves of COVID-19, and patients with neurocovid exhibited a higher susceptibility to adverse outcomes compared to other COVID-19 patients. Among all neurological syndromes, vascular syndromes were the most common, and their severity surpassed that of vascular syndromes not attributed to COVID-19.

HTLV-1 is an enigmatic retrovirus triggering a debilitating neuroinflammatory disease, HTLV-1-associated myelopathy (HAM), with unknown pathogenesis. Both HTLV-1 infection and HAM predominantly affect women and non-white neglected populations. HAM is lacking disease-modifying treatment, as current treatment is mostly symptomatic and inspired by either HIV-1 or multiple sclerosis therapeutic strategies. We used systems biology analyses of novel and publicly available data comprising (epi)genomics, transcriptomics, metabolomics and proteomics of multi-ancestry cohorts from a total of > 2500 People Living with HTLV-1 from 5 countries (Brazil, Peru, Japan, UK, US). Leveraging an unique admixed Brazilian cohort, genome-wide association study (GWAS) revealed African-specific variants in inflammasome sensor AIM2 with genome-wide significance (p < 5x10-8). Suggestive loci (p > 5x10-8) corresponding to metabolic, immune and neuronal genes were validated using published Japanese GWAS. Polygenic risk score and proviral load were independent disease predictors across ancestries. Systems biology analysis revealed neuronal/synaptic signaling, monocyte count, glucose/lipid metabolism, and neurocognition/depression as genetically linked to HAM. In silico drug screening identified estrogen blocker Fulvestrant as the top hit, while also confirming existing (pre)clinical data for HDAC inhibitors and immunosuppressants. Validated GWAS genes were overexpressed in HAM patients' whole blood and CD4 T-cells, as well as in spinal cord astrocytes, oligodendrocytes, and microglia by single-cell RNAseq. We experimentally confirmed decreased ApoA1/lipid/cholesterol levels, higher monocyte levels and lower neurocognitive scores in multi-ancestry cohorts. We found striking biological similarities between retroviral Hbz/Tax overexpression, Hbz interactome and HAM multi-omics findings: enrichment for lipid/cholesterol metabolism, estrogen signaling, neurodegenerative diseases, and viral pathways including EBV, recently identified as the major driver of multiple sclerosis. In conclusion, our data-driven approach uncovers novel disease mechanisms and therapeutic targets, and a validated polygenic risk score allowing targeted surveillance for high-risk individuals. A strong molecular overlap to other neurodegenerative/neuroinflammatory diseases reveals shared neuropathogenic pathways between unrelated viruses.

The Cognitive Function Index (CFI) was developed to identify individuals with Subjective Cognitive Decline (SCD), which is defined by the self-perception of cognitive impairment, not detected in neuropsychological tests. Limited research has been done with this tool in Latin America (LA). We aimed to investigate the association between CFI and global cognition and to investigate whether CFI scores can identify participants with cognitive performance below 1.0 standard deviation (SD) of the sample mean. The LatAm-FINGERS study is a dementia prevention feasibility study in 12 LA countries. For the present analysis, 815 participants with complete cognitive data (604 women, 74.1%; 436 mestizo 53.5%; mean age=67.5, SD=4.8; mean education = 13.0, SD=3.6; mean GDS=2.7, SD=2.8) were included. The CFI is a 14-item self-report measure of cognitive change; higher scores indicate higher concerns. CFI total score was normalized into a z-score, as some questions were not applicable to all participants and total score differed among them. Cognition was assessed with the Preclinical Alzheimer Cognitive Composite (PACC-5) - Mini-Mental State Examination; Logical Memory Delayed Recall; Free and Cued Selective Reminding Test; Digit Symbol Substitution Test; and Animal Category Fluency. Participants were classified into those with PACC-5 at or above 1 SD from the mean ( n  = 764) and those below ( n  = 51). Bivariate and partial correlations (controlling for sex, age, education and GDS score) were used to assess the association between the CFI and PACC-5 scores. Receiver operating characteristic (ROC) analyses were used to assess CFI accuracy to identify participants with PACC-5 scores below 1 SD. CFI and PACC-5 scores were negatively associated with each other ( r  =  -0.27; p  <0.001; partial r = -0.12; p  <0.001). ROC analyses indicated an area under the curve (AUC) of 0.71 (sensitivity=0.64; specificity=0.70) with an optimal threshold of 0.36 (Youden Index=0.35) as a suggested cutoff score for the normalized CFI score. The CFI may be added to cognitive screening protocols to identify individuals who may need further assessment. Integrating the CFI into screening strategies in LA could play a pivotal role in reducing cognitive health disparities and advancing tailored dementia prevention initiatives that address the region's specific sociocultural and healthcare challenges.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997–2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurological and clinical manifestations that do not meet diagnostic criteria for HAM. These conditions may later progress to HAM or constitute an intermediate clinical form: intermediate syndrome (IS), a mid-point between asymptomatic HTLV-1 carriers and those with full myelopathy. Thus, we determined the incidence of HAM cases in the HTLV-1-asymptomatic and IS patients, and the clinical/laboratory associated markers. A total of 204 HTLV-1-positive patients were included in this study, divided into two groups: Group 1, including 145 asymptomatic HTLV-1 subjects (ASY), and Group 2, including 59 patients with inflammatory clinical symptoms in more than three systems and a high proviral load (PVL). During a 60-month follow-up time, with the age ranging from 47 to 79 years, ten patients of the fifty-nine initially diagnosed as IS developed HAM (iHAM), and two patients of the initial 145 ASY developed HAM directly. Women were more prevalent in all groups. For the iHAM patients, the age ranged from 20 to 72 years, with a mean of 53 (±15 SD). Older age was associated with the development of HAM, higher PVL and IS; however, there was no any specific symptom or clinical sign, that was associated with risk for iHAM. In conclusion, IS cases could be an early phase of development of HAM. These findings show the presence of higher incidence probabilities in our cohort than previously reported.

Background. Mother-to-child transmission (MTCT) of human T-lymphotropic virus type 1 (HTLV-1) is an important route of transmission that can cause lifelong infection. There is high morbidity and mortality due to adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy (HAM), and other inflammatory disorders. These conditions develop in nearly 10% of people with HTLV-1 infection, with a higher risk if infection occurs early in life. Identification of risk factors can inform targeted measures to reduce HTLV-1 MTCT. This study aimed to investigate the potential of cesarean delivery to prevent HTLV-1 MTCT. Methods. We performed a review of the cases of women and their offspring under regular follow-up at the HTLV-1 outpatient clinic at the Institute of Infectious Diseases Emilio Ribas. Results. A total of 177 HTLV-1-infected women and 369 adult offspring were investigated. Overall, 15% of the children were positive for HTLV-1 and 85% were negative. Regarding vertical transmission, we found that a breastfeeding duration of >6 months was associated with MTCT. Moreover, maternal proviral load was not associated with transmission, but high educational level and cesarean delivery were identified as protective factors. Conclusions. HTLV-1 MTCT was associated with mother's age at delivery of >25 years, low educational level, prolonged breastfeeding, and vaginal delivery.

Background: During the development of human T-cell lymphotropic virus (HTLV-1)-associated myelopathy (HAM), the inflammatory phenomenon is very prominent and is a major factor in the outcome of the disease. The use of corticosteroids can modify their natural history, and in this study, we evaluated the effectiveness of using daily low-dose prednisone. Methods: This was a cross-sectional study using data collected by physicians monitoring patients with HAM at the Institute of Infectious Diseases “Emilio Ribas”, the main referral center for patients with infectious diseases in São Paulo, Brazil. The objective was to determine if daily low-dose oral prednisone would be able to stabilize the progression of HAM. The outcome measure was a change in the Osame Motor Disability Score (OMDS). Results: Fifty-four patients used treatment with oral prednisone, 5 milligrams daily. Nine cases were excluded from the study because they did not have at least two rating scales within a minimum interval of one year, and six were excluded for being co-infected with HIV and/or HCV. Thirty-nine patients met this criterion and were included for analysis. The majority were women (71.8%), the mean age was 56.51 years old (SD ± 9.74), and the median time of use of prednisone was 16 months. Thirty-two patients (82.05%) maintained the same OMDS, 5/39 (12.82%) had clinical worsening, and 2/39 (5.13%) improved. Conclusions: There was a trend toward clinical stability with the use of oral corticosteroids. However, randomized controlled trials are necessary to evaluate the use in clinical practices in all stages of HAM.