Search

Competing Interests: Authors declare no conflict of interest.

The human T-cell lymphotropic virus type 1 (HTLV-1) is a single-stranded positive-sense RNA virus that belongs to the Retroviridae family, genus Deltaretro, and infects approximately five to 10 million people worldwide. Although a significant number of individuals living with HTLV-1 remain asymptomatic throughout their lives, some develop one or more severe clinical conditions, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive and debilitating disease, and/or a subtype of non-Hodgkin's lymphoma with a more threatening course known as adult T-cell leukemia/lymphoma (ATLL). Moreover, current therapeutic options are limited and focus primarily on treating symptoms and controlling viral latency. CRISPR-Cas9 gene editing is proposed as a promising tool to address the intricate links associated with HTLV-1. By targeting or silencing key genes during initial infection and dysregulating immune signaling pathways, CRISPR-Cas9 offers potential intervention opportunities. In this review, we address the therapeutic potential of CRISPR-Cas9 gene editing, as well as examine the primary mechanisms involved in editing potential target genes and discuss the existing evidence in the current scientific literature.

The presence of genetic mutations in HIV poses a significant challenge, potentially leading to antiretroviral resistance and hampering therapeutic development. The Brazilian population has presented variations in the HIV envelope V3 loop gene, especially the GWGR motif. This motif has been linked to reduced transmission potential and slower CD4+ T cell decline. This study aimed to assess clinical outcomes in patients with HIV-1 infected with strains containing the GWGR motif compared with those without it during long-term cART. A cohort of 295 patients with HIV was examined for the GWGR motif presence in the V3 loop. A total of 58 samples showed the GWGR signature, while 237 had other signatures. Multifactorial analyses showed no significant differences in demographic characteristics, CD4+ cell count, AIDS progression, or mortality between GWGR carriers and others. However, the mean interval between the first positive HIV test and the initial AIDS-defining event was more than two times longer for women carrying the GWGR signature (p = 0.0231). We emphasize the positive impact of cART on HIV/AIDS treatment, including viral suppression, CD4+ cell preservation, and immune function maintenance. Although no significant differences were found during cART, residual outcomes reflecting adherence challenges were observed between diagnosis and the first AIDS-defining event. The previously described outcomes, highlighting statistically significant differences between individuals carrying the GPGR motif compared with those with the Brazilian GWGR motif, may be directly linked to the natural progression of infection before advancements in cART. Presently, these physicochemical aspects may no longer hold the same relevance.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Assone, Menezes, Gonçalves, Folgosi, Braz, Smid, Haziot, Marcusso, Dahy, de Oliveira, Vanderlinden, Claes, Daelemans, Vercauteren, Schols, Casseb and Van Weyenbergh.)

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., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes severe diseases, such as aggressive cancer or progressive neurological disease. HTLV-1 affects mainly people in areas with low human development index and can be transmitted from mother to child, primarily through breastfeeding. Refraining from breastfeeding is an effective intervention to reduce the risk of infection in infants. However, HTLV-1 antenatal screening is not offered globally. According to WHO, the scarcity of cost-effectiveness studies is considered one of the major barriers to the implementation of policies to prevent HTLV-1 infection. Therefore, this study aimed to assess the cost-effectiveness of antenatal screening and postnatal interventions to prevent HTLV-1 mother-to-child transmission in Brazil and to develop an open-access, editable, mathematical model that can be used by other countries and regions to assess different scenarios., Methods: In this cost-utility analysis, we constructed a decision tree and a Markov model to assess the cost-effectiveness of HTLV-1 antenatal screening and postnatal interventions (ie, avoidance of breastfeeding, by suppression of lactation with cabergoline, and provision of formula feed) to reduce transmission. For our model, we used data from Brazil and we took the perspective of the public health-care system to estimate costs., Findings: The implementation of both screening and interventions would result in the prevention of 1039 infections in infants every year in Brazil with an incremental cost-effectiveness ratio (ICER) of US$11 415 per quality-adjusted life-year (QALY). 88% of all probabilistic sensitivity analysis simulations had ICER values lower than the Brazilian cost-effectiveness threshold ($18 107·74 per QALY). HTLV-1 prevalence in pregnant women, the risk of HTLV-1 transmission when breastfeeding lasts for 6 months or more, and the cost of screening tests were the variables with the largest effect on ICER., Interpretation: HTLV-1 antenatal screening is cost-effective in Brazil. An open-access model was developed, and this tool could be used to assess the cost-effectiveness of such policy globally, favouring the implementation of interventions to prevent HTLV-1 mother-to-child transmission worldwide., Funding: None., Translations: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests LC reports receipt of funding from AbbVie, Roche, and AstraZeneca for participation in advisory boards, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors., Patients and Methods: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1 NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification., Results: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP., Conclusions: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP., (© 2022. The Author(s).)

Background: Knee osteoarthritis (OA) is a leading cause of disability in the elderly population. Chronic disabling pain is associated with maladaptive neuroplastic changes in brain networks, commonly associated with central sensitization. The main clinical features of nociplastic pain conditions include combined peripheral and central sensitization, and it is crucial to recognize this type of pain, as it responds to different therapies than nociceptive and neuropathic pain., Objective: To report the effect of the Institute of Physical Medicine and Rehabilitation (IMREA) comprehensive rehabilitation program to reduce pain and to improve functioning in elderly people with knee OA, under the DEFINE cohort., Methods: This is a retrospective observational cohort of 96 patients with knee OA, recruited from October 2018 to December 2019. All patients were evaluated by a trained multidisciplinary team using the Kellgren Lawrence classification, bilateral knee ultrasonography, the visual analog scale (VAS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, rigidity and difficulty scores, the Timed Up and Go Test (TUG), 10-m and 6-min walking test (10 and 6 MWT), Berg Balance Scale, isokinetic dynamometry for knee extension and flexion strength, and pain pressure thresholds. The rehabilitation program included paraspinous lidocaine blocks, focal extracorporeal shockwaves combined with radial pressure waves and functional electrical stimulation according to individual needs. The baseline was compred with the treatment results with a paired t -test., Results: The study sample is composed of 96 participants, mostly females ( n = 81, 84.38%), with bilateral osteoarthritis ( n = 91, 94.79%), and a mean age of 68.89 (SD 9.73) years. Functional improvement was observed in TUG ( p = 0.019), 6-mwt ( p = 0.033), right knee flexion strength ( p < 0.0001), WOMAC rigidity and difficulty domains ( p < 0.0001). Pain was reduced from baseline as measured by WOMAC pain domain ( p < 0.0001), VAS for both knees ( p < 0.0001), and SF-36 pain domain ( p < 0.0001). Pressure pain threshold was modified above the patella ( p = 0.005 and p = 0.002 for right and left knees, respectively), at the patellar tendons ( p = 0.015 and p = 0.010 for right and left patellar tendons, respectively), left S2 dermatome ( p = 0.017), and L1-L2 ( p = 0.008)., Conclusions: The IMREA comprehensive rehabilitation program improved functioning and reduced disabling pain in elderly people with knee OA. We highlight the relevance and discuss the implementation of our intervention protocol. Although this is an open cohort study, it is important to note the significant improvement with this clinical protocol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Imamura, Shinzato, Sugawara, Uchiyama, Matheus, Simis, Ayres, dos Santos, Assone, Ramos, Fregni and Battistella.)

Interferon-gamma (IFN-γ) plays a crucial role in viral infections by preventing viral replication and in the promotion of innate and adaptive immune responses. However, IFN-gamma can exert distinct effects in different persistent viral infections. The long-term overproduction of IFN-γ in retroviral infections, such as the human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), and human endogenous retroviruses (HERVs), resulting in inflammation, may cause neuronal damage. This review is provocative about the role of IFN-γ during persistent retroviral infections and its relationship with the causation of some neurological disorders that are important for public health.

Human T cell lymphotropic virus (HTLV) is the caustive agent of two main conditions i. e., the HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and the adult T-cell leukemia/lymphoma (ATLL). HTLV diagnosis is based on serological and molecular approaches; however, an accurate and validated method is still needed. The objective of this study was to establish a rapid and sensitive molecular test to confirm and discriminate HTLV 1/2 types. The test validation was performed as a multicentric study involving HTLV confirmation centers throughout Brazil. Proviral DNA was extracted from whole blood and the amplification was performed using in-house designed primer and probe sets targeting the pol genomic region. An internal control to validate the extraction and amplification was also included. The limit of detection (LoD) of the assay was four copies/reaction for HTLV-1 and 10.9 copies/reaction for HTLV-2. The diagnostic sensitivity of the platform was 94.6% for HTLV-1, 78.6% for HTLV-2, and the specificity was 100% for both viruses. Cross-reactions of the test with human viruses including HAV, HBV, HCV, HIV-1/2, and parvovirus B19 were not observed. During the multicentric validation, the test was used to screen a total of 692 blood samples obtained from previously confirmed HTLV-positive individuals. From these, 91.1% tested positive being concordant with the previously obtained results. In conclusion, our duoplex-RT-PCR-HTLV1 /2 presented adequate efficiency for HTLV-1/2 differentiation showing high sensitivity and specificity. Therefore, it can be a suitable tool for confirmation of suspected and inconclusive HTLV cases, prenatal and pre-transplant diagnosis, in Brazil and in other countries HTLV-endemic countries., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rocha-Junior, Rodrigues, Slavov, Assone, Pedreschi, de La Roque, Sousa, Olavarria, Galvão-Castro, Fonseca, Penalva de Oliveira, Smid, Takayanagui, Casseb, Covas and Kashima.)

Competing Interests: CR and TA are co-founders of HTLV Channel, a non-profit self-funded platform by HTLV Channel. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Human T lymphotropic virus 1 (HTLV-1) is a public health issue for most countries and imposes important consequences on patients' health and socioeconomic status. Brazil is one of the global leaders of the public health response to these viruses. The country has challenges to overcome to implement meaningful policies aiming to eliminate HTLV-1/2. An analysis of strengths, weaknesses, opportunities, and threats (SWOT) for the implementation of public health policies on HTLV-1/2 was performed. The strengths identified were the Brazilian Unified Health System (SUS); Brazilian expertise in public health programs successfully implemented; currently available policies targeting HTLV; and strong collaboration with researchers and patient's representative. Lack of awareness about HTLV, insufficient epidemiological data, lack of reference centers for patient care, insufficient availability of confirmatory tests, lack of universal antenatal screening, and absence of cost-effectiveness studies were identified as weaknesses. Some interesting opportunities included the increased interest from international organizations on HTLV, possibility of integrating HTLV into other programs, external funding for research, available online platforms, opportunity to acquire data from HTLV-1/2 surveillance to gather epidemiological information, and HTLV policies that were implemented independently by states and municipalities. In addition to the COVID-19 pandemic, existing demands from different diseases, the country's demography and its marked sociocultural diversity and the volatility of the technical team working with HTLV-1/2 at the Brazilian Ministry of Health are threats to the implementation of public policies on HTLV-1/2. This SWOT analysis will facilitate strategic planning to allow continuous progress of the Brazilian response to HTLV-1/2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miranda, Rosadas, Assone, Pereira, Vallinoto and Ishak.)

Human T-cell lymphotropic viruses 1 and 2 (HTLV-1/2) are relatively common in Brazil but remain silent and neglected infections. HTLV-1 is associated with a range of diseases with high morbidity and mortality. There is no curative treatment for this lifelong infection, so measures to prevent transmission are essential. This narrative review discusses HTLV-1/2 transmission routes and measures to prevent its continuous dissemination. The public health policies that are currently implemented in Brazil to avoid HTLV-1/2 transmission are addressed, and further strategies are proposed., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Brazil has a high number of HTLV-1/2 infections which are unequally distributed in the country. Most prevalence studies have focused on specific populations, such as blood donors and pregnant women. Some areas, for example the state of Bahia, have robust information about HTLV-1/2 infection, however there is no information available about this infection in the general population of Vitória, Espírito Santo, Brazil., Objective: To determine the prevalence of HTLV-1/2 infection in adults from the municipality of Vitoria, ES., Methods: A cross sectional study was performed from September 2010 to December 2011, in individuals of both sexes, aged 18 or older living in Vitória-ES. Venous blood samples were collected and tested for anti-HTLV-1/2 antibodies by chemiluminescent immunoassay (CMIA). Individuals with CMIA reactive results were submitted to a new blood collection for retesting by CMIA, followed by PCR to confirm infection and discriminate the viral type., Results: From 1502 tested samples, eight were reactive in CMIA and all were confirmed by PCR. Therefore, the prevalence of HTLV-1/2 was 0.53% (8/1502, 95% CI: 0.2-1.0%). The infection rate was 0.7% in men (5/711, 95% CI: 0.17-1.51%), and 0.38% in women (3/791, 95% CI: 0-0.81%)., Conclusions: The prevalence of HTLV-1/2 infection was 0.53% (8/1502; 95% CI: 0.2-0.9%). Confirmatory test using real-time PCR (qPCR) identified seven individuals positive for HTLV-1 and one for HTLV-2. Considering the risk of infected individuals to develop high morbidity and mortality diseases, it would be important to implement public health policies aimed at stopping transmission of these viruses in this municipality., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2021 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Few studies have reported the prognosis of human immunodeficiency virus (HIV)-positive patients followed for a long time in Brazil, particularly those including pre and post-HAART eras. The polymorphisms of interferon (IFN)-λ4 have been postulated as possibly associated with the pathogenesis of HIV infection. The aim of this study was to describe the incidence and mortality from a cohort of HIV-positive patients as well as whether IFN-λ4 gene polymorphisms (SNP rs8099917 and SNP rs12979860) were associated with HIV/acquired immune deficiency syndrome (AIDS) progression. We followed 402 patients for up to 30 years; 347 of them began follow-up asymptomatic, without any AIDS-defining opportunistic disease and/or a lymphocytes T CD4+ count of 350 cells/mm 3 or lower. We determined the probability of the asymptomatic subjects to remain AIDS-free, and the risk of death for those entering the study already with an AIDS diagnosis, as well as for subjects developing AIDS during follow-up. We compared the prognosis of patients with two different polymorphisms for the genes encoding for IFN-λ4, variants rs8099917 and rs12979860. The follow-up time of the 347 asymptomatic-at-entry subjects was 3687 person-years. IFN-λ4 rs8099917 polymorphisms were not associated with AIDS progression, but IFN-λ4 rs12979860 wild type genotype (CC) was associated with higher mortality compared to CT and TT, with an increased probability of death from AIDS (P = .01). In conclusion, genetic variations in IFN-λ4 on rs12979860 polymorphisms in HIV-infected patients may drive mortality risk., (© 2020 Wiley Periodicals LLC.)

The human T cell lymphotropic virus type 1 (HTLV-1) is the first human retrovirus discovered. Since then, it has spread worldwide and is mainly associated with adult T cell leukemia/lymphoma (ATLL) and HTLV1-associated myelopathy (HAM). Its relationship, however, with other types of cancer is controversial. We describe the case of a patient presenting with small cells lung epidermoid carcinoma who had recently developed HAM, and a review of the literature related to these conditions. This is the first case of this type of lung cancer, the same of the first description in the literature, associated with HAM outside Japan.

Background: Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated not only with some severe manifestations, such as HTLV-1-associated myelopathy (HAM) and ATLL, but also with other, less severe conditions. Some studies have reported neurologic manifestations that did not meet all the criteria for the diagnosis of HAM in individuals infected with HTLV-1; these conditions may later progress to HAM or constitute an intermediate clinical form, between asymptomatic HTLV-1 carriers and those with full myelopathy. This study evaluated the prognostic value and looked for a possible association of those parameters with the intermediate syndrome (IS) status and HAM status., Methods: Proviral load (PVL), spontaneous lymphoproliferation, interferon (IFN)-γ spontaneous production was quantified in samples of asymptomatic and HAM patients, as well as patients with IS., Results: The critical age range was 50-60 years for IS outcome and more of 60 years for HAM outcome, with an increased risk of 2.5-fold for IS and 6.8-fold for HAM. IFN-γ was increased in patients with IS compared with asymptomatic carriers (ACs) ( p = 0.007) and in patients with HAM compared with ACs ( p = 0.03). Lymphoproliferation was increased in patients with HAM vs ACs ( p = 0.0001) and patients with IS ( p = 0.0001). PVL was similar between groups., Conclusion: IFN-γ has high specificity of prediction of subject remain asymptomatic compared with PVL and lymphoproliferation assay tests. IFN-γ has been shown to be a biomarker of progression to intermediate stage and to HAM. The association of other markers with manifestations associated with HTLV-1 infection that does not meet the HAM criteria should be verified., (© 2020 American Academy of Neurology.)

Background: HTLV-1 is a neglected sexually transmitted infection despite being the cause of disabling neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is no treatment for this infection and public health policies are essential to reduce its transmission. However, there are no data to support adequate cost-effective analysis in this field. The aim of this study was to obtain health state utility values for individuals with HAM/TSP and HTLV-1 asymptomatic carriers (AC). The impact of both states on quality of life (QoL) is described and compared to other diseases., Methods: A cross-sectional observational study of 141 individuals infected with HTLV-1 (79 with HAM/TSP and 62 AC) from three Brazilian states (Rio de Janeiro, São Paulo and Alagoas) and from the United Kingdom. Participants completed a validated general health questionnaire (EQ-5D, Euroqol) from which country specific health state utility values are generated. Clinical and epidemiological data were collated., Principal Findings: Health state utility value for HAM/TSP was 0.2991. QoL for 130 reported clinical conditions ranges from 0.35 to 0.847. 12% reported their quality of life as worse as death. Low QoL was associated with severity rather than duration of disease with a moderate inverse correlation between QoL and Osame's Motor Disability Score (-0.4933) Patients who are wheelchair dependent had lowest QoL whilst those still walking unaided had the highest. AC also reported impaired QoL (0.7121) compared to general population., Conclusion: HTLV-1 and its associated neurological disease has a marked impact on QoL. This study provides robust data to support the development of cost-utility analysis of interventions for HTLV-1., Competing Interests: The authors have declared that no competing interests exist.

Background: Despite its relatively low incidence of associated diseases, Human T-cell Leukemia Virus-1 (HTLV-1) infection was reported to carry a significant risk of mortality in several endemic areas. HTLV-1-associated diseases, adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraperesis (HAM/TSP), as well as frequent coinfections with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Strongyloides stercoralis were associated to increased morbidity and mortality of HTLV-1 infection. Objective: To determine the mortality rate and its associated variables from an open cohort started in July 1997 at the HTLV Clinic, Emilio Ribas Institute (IIER), a major infectious disease hospital in São Paulo, Brazil. Methods: Since inception up to September 2018, we admitted 727 HTLV-1-infected individuals, with a rate of 30-50 new admissions per year. All patient data, including clinical and laboratory data, were regularly updated throughout the 21-year period, using a dedicated REDCap database. The Ethical Board of IIER approved the protocol. Results: During 21 years of clinical care to people living with HTLV-1 in the São Paulo region, we recruited 479 asymptomatic HTLV-1-infected individuals and 248 HAM/TSP patients, of which 632 remained under active follow-up. During a total of 3800 person-years of follow-up (maximum follow-up 21.5 years, mean follow-up 6.0 years), 27 individuals died (median age of 51.5 years), of which 12 were asymptomatic, one ATLL patient and 14 HAM/TSP patients. HAM/TSP diagnosis (but neither age nor gender) was a significant predictor of increased mortality by univariate and multivariate (hazard ratio (HR) 5.03, 95% CI [1.96-12.91], p = 0.001) Cox regression models. Coinfection with HIV/HCV was an independent predictor of increased mortality (HR 15.08; 95% CI [5.50-41.32]; p < 0.001), with AIDS-related infections as a more frequent cause of death in asymptomatics (6/13; p = 0.033). HIV/HCV-negative fatal HAM/TSP cases were all female, with urinary tract infection and decubitus ulcer-associated sepsis as the main cause of death (8/14, p = 0.002). Conclusions: All-cause mortality among people living with HTLV-1 in São Paulo differs between asymptomatic (2.9%) and HAM/TSP patients (7.3%), independent of age and gender. We observe a dichotomy in fatal cases, with HAM/TSP and HIV/HCV coinfection as independent risk factors for death. Our findings reveal an urgent need for public health actions, as the major causes of death, infections secondary to decubitus ulcers, and immune deficiency syndrome (AIDS)-related infections, can be targeted by preventive measures.

Background: Although classical human T-cell lymphocyte virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis syndrome is the most frequent HTLV-1-associated neurological disorder, some "minor" neurological disorders can be seen in "asymptomatic" carriers. These disorders, including cognitive alterations already described in clinical cases and studies, may constitute an intermediate syndrome (IMS) between the asymptomatic state and myelopathy. The aim of this study was to investigate the presence of cognitive deficits in patients with HTLV-1 virus, who usually are diagnosed as asymptomatic., Methods: A total of 54 HTLV-1-infected patients were evaluated, 35 asymptomatic and 19 with minor neurological alterations (evaluated by a neurologist); 25 HTLV-1-seronegative individuals served as controls. The instruments used were: Beck's Depression Inventory, Lawton's Daily Life Activity Scale, and a complete neuropsychological battery. The application of these evaluation instruments was performed blindly, with the evaluator neuropsychologist not knowing the clinical condition of the patient., Results: Most of the participants in this cohort, including seronegative controls, were female (n = 57, 72.21%), their mean age was 52.34 years (SD = 14.29) and their average schooling was 9.70 years (SD = 4.11)., Discussion: Participants classified with IMS had lower gross scores when compared with both the patients classified as asymptomatic and with the control group, and when tested for auditory episodic memory of immediate (p < 0.01), and late (p = 0.01), recall., Conclusion: Patients with IMS presented with memory impairment when compared with asymptomatic patients and seronegative individuals; this is one of the symptoms that aids in the classification of the syndrome.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurologic manifestations that do not meet diagnostic criteria for HAM/TSP. These conditions may later progress to HAM/TSP or constitute an intermediate clinical form, between asymptomatic HTLV-1 carriers and those with full myelopathy. Our aim was to determine the prevalence of HTLV-1-associated disease in subjects without HAM/TSP, and the relationship between these findings with HTLV-1 proviral load (PVL)., Methods: 175 HTLV-1-infected subjects were submitted to a careful neurological evaluation, during their regular follow up at the HTLV outpatient clinic of the Institute of Infectious Diseases "Emilio Ribas", São Paulo city, Brazil. Clinical evaluation and blinded standardized neurological screening were performed for all the subjects by the same neurologist (MH)., Results: After the neurological evaluation, 133 patients were classified as asymptomatic and 42 fulfilled the criteria for intermediate syndrome (IS). The mean age of the enrolled subjects was 46.3 years and 130 (74.3%) were females. Clinical classification shows that neurological symptoms (p<0.001), visual disorders (p = 0.001), oral conditions (p = 0.001), skin lesions (p<0.001), bladder disorders (p<0.001), and rheumatological symptoms (p = 0.001), were strongly associated to IS, except for disautonomy (p = 0.21). A multivariate analysis revealed that HTLV-1 proviral load, oral conditions, bladder disorders and rheumatological symptoms were independently associated with the IS., Conclusions: We found some early alterations in 42 patients (24%), particularly the presence of previously not acknowledged clinical and neurological symptoms, among subjects previously classified as "asymptomatic", who we reclassified as having an intermediate syndrome., Competing Interests: No. The authors have declared that no competing interests exist.

HTLV-1 is transmitted primarily either through sexual intercourse or from mother to child. The mother/child pairs were classified as seroconcordant or serodiscordant. We analyzed mother to child transmission (MTCT) according to sociodemographic, clinical and epidemiological characteristics of the mother, child's gender and duration of breastfeeding. Between June 2006 and August 2016 we followed 192 mothers with HTLV-1 infection (mean age 41 years old), resulting in 499 exposed offspring, 288 (57.7%) of whom were tested for HTLV-1, making up the final sample for the study, along with their 134 respective mothers. Among the tested mother/child pairs, 41 (14.2%) were HTLV-1 positive, highlighted that seven of 134 family clusters concentrated 48.8% of positive cases. Variables associated with a positive child: breastfeeding duration ≥12 months, maternal PVL ≥100 copies/10 4 PBMC, mother's age at delivery >26 years old, and HTLV-1 in more than one child of the same mother. In a multiple logistic regression, breastfeeding ≥12 months, higher maternal PVL and ≥2 previous HTLV-1-infected children remained independently associated with the outcome. Thus, high maternal PVL and breastfeeding beyond 12 months were independently associated with MTCT of the HTLV-1 infection. Our results reinforce the need for both prenatal HTLV screening in endemic areas and for advising mothers on breastfeeding.

Background: Infection with Human T cell Leukemia Virus type 1 can be associated with myelopathy/tropical spastic paraparesis (HAM/TSP) and other inflammatory diseases. Lymphocytes from about half of Human T cell Leukemia Virus type 1-infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease and viral burden is poorly understood., Objective: To evaluate T-cell proliferation in vitro among patients co-infected with Human T cell Leukemia Virus type 1/Hepatitis C Virus/Human Immunodeficiency Virus type 1., Material and Methods: From 610 Human T cell Leukemia Virus-infected patients of the Human T cell Leukemia Virus outpatient clinic from Institute of Infectious Diseases "Emilio Ribas" in São Paulo, 273 agreed to participate: 72 had HAM/TSP (excluded from this analysis) and 201 were asymptomatic, a classification performed during a regular neurological appointment. We selected the subgroup made up only by the 201 asymptomatic subjects to avoid bias by the clinical status as a confounder effect, who had laboratory results of Human T cell Leukemia Virus type 1 proviral load and T-cell proliferation assay in our database. They were further grouped according to their serological status in four categories: 121 Human T cell Leukemia Virus type 1 asymptomatic mono-infected carriers; 32 Human T cell Leukemia Virus type 1/Hepatitis C Virus, 29 Human T cell Leukemia Virus type 1/Human Immunodeficiency Virus type 1, and 19 Human T cell Leukemia Virus type 1/Human Immunodeficiency Virus type 1/Hepatitis C Virus co-infected patients. Clinical data were obtained from medical records and interviews. DNA Human T cell Leukemia Virus type 1 proviral load (PVL) and T-cell proliferation (LPA) assay were performed for all samples., Results: From a total of 273 subjects with Human T cell Leukemia Virus type 1, 80 presented co-infections: 29 had Human Immunodeficiency Virus type 1, 32 had Hepatitis C Virus, and 19 had Human Immunodeficiency Virus type 1 and Hepatitis C Virus. Comparing the groups based on their serological status, independently of being asymptomatic carriers, we observed a significant increase of PVL (p<0.001) and LPA (p=0.001). However, when groups were stratified according to their clinical and serological status, there was no significant increase in Human T cell Leukemia Virus type 1 PVL and LPA., Conclusion: No significant increase of basal T-cell proliferation among Human T cell Leukemia Virus type 1 co-infected was observed. This interaction may be implicated in liver damage, worsening the prognosis of co-infected patients or, on the contrary, inducing a higher spontaneous clearance of Hepatitis C Virus infection in Human T cell Leukemia Virus type 1 co-infected patients., (Copyright © 2018 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: Several genetic polymorphisms may be related to susceptibility or resistance to viral disease outcomes. Immunological or genetic factors may act as major triggers of the immune pathogenesis of HAM/TSP. This study investigated the association of immune related genetic polymorphisms with viral and immunological markers., Methods: 247 HTLV-1-infected volunteers, drawn from a larger group of HTLV-infected subjects followed at the Institute of Infectious Diseases "Emilio Ribas" (IIER) for up to 19 years, participated in this study, which ran from June 2011 to July 2016. The subjects were classified according to their neurological status into two groups: Group 1 (160 asymptomatic individuals) and Group 2 (87 HAM/TSP patients). Samples were tested for spontaneous lymphocyte proliferation (LPA) and HTLV-1 proviral load (PVL) and for IFN-λ4, HLA-C and KIR genotypes using qPCR., Results: We found associations between LPA (p=0.0001) with HAM/TSP and confirmed the IFN-λ4 polymorphism rs8099917, allele GG, as a protective factor using a recessive model (OR=3.22, CI=1.10-9.47). Polymorphisms in HLA-C and KIR alleles were not associated with risk of developing HAM/TSP., Conclusion: We demonstrated that age, LPA and an IFN-λ4 polymorphism were associated with progression to HAM/TSP. Understanding HAM/TSP pathogenesis can provide important markers of prognostic value for clinical management, and contribute to the discovery of new therapeutic interventions in the future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Decrease in bone mineral density (BMD) has been a complication among people living with HIV/AIDS. To investigate the prevalence of osteopenia/osteoporosis among HIV-infected people living in São Paulo city, we studied 108 HIV-infected patients (79 men and 29 women). We extracted data from patients' medical records and BMD was measured by dual-energy X-ray absorptiometry (DXA). Median age of participants was 42 years (interquartile range [IQR] 36-48 years), and the median time since HIV diagnosis was 4.01 years (IQR 2-11 years). Patients had acquired HIV primarily by the sexual route (men who have sex with men 44%, heterosexual 49%). Median age, duration of HIV infection, duration of ART and CD4 nadir were similar for men and women. Plasma viral load was undetectable for 53 patients (49%). Median CD4 T cell count was 399 cells/µL (IQR 247 - 568). Twenty five patients (23%) had LBMD, and there was no statistically significant difference between men and women (<-1). The associated risk factors for LBMD were older age (≥ 50 years old) and smoking with a RR of 3.87 and 2.80, respectively. Thus, despite the lack of statistically significant relationship between the use of ART and LBMD or between duration of ART and LBMD, these factors should be addressed in larger studies.

Human T-cell lymphotropic virus type 1 is transmitted primarily either through sexual intercourse or from mother to child. The current study investigated sexual transmission and compared the HTLV-1 proviral load between seroconcordant and serodiscordant couples by examining both men and women among the index partners without using subjective criteria to establish the direction of sexual transmission. Between January 2013 and May 2015, 178 HTLV-1-positive patients had spouses, 107 of which had tested partners, thus increasing the initial sample size (46 men and 61 women). Individuals co-infected with HTLV-2 or human immunodeficiency virus were not included in the analysis. From among the included participants, 26 men and 26 women were paired with each other, resulting in 26 seroconcordant couples; 12 seroconcordant couples were formed from another four men and eight women. Forty-three serodiscordant couples were formed from 16 men and 27 women. The rate of seroconcordance was 46.9%. The HTLV-1 proviral load was compared between 19 and 37 seroconcordant and serodiscondant couples, respectively, and the concordant couples showed higher proviral loads (P = 0.03). There were no differences between the groups according to age, relationship length, having a mother or sibling with HTLV-1, race, ethnicity, nationality, education, history of blood transfusion, HAM/TSP, ALT, or hepatitis C virus status. In multivariate analysis, relationship time was shown associated with ocurrence of seroconcordance status. The apparent association between high circulating levels of provirus and seroconcordance rate among couples suggests that proviral loads contribute markedly to the risk of sexual transmission, regardless of gender index., (© 2016 Wiley Periodicals, Inc.)

Introduction: Infection with Human papillomavirus (HPV) has been reported as one of the most prevalent agent sexually transmitted diseases, but its true prevalence in men is not precisely known, mainly due to the near absence of symptoms. Moreover, few studies evaluating the post-vaccination immune response have been performed to date in men, hence the hypotheses tested in this study can be important to enable a better understanding of both the immunopathogenesis and the response to vaccination in HIV-infected patients, and to help in the elaboration of strategies of vaccination against HPV in the HIV-infected population., Objectives: To analyze the specific response to antigens of HPV vaccine in HIV-infected men., Methods: A total of 25 HIV-infected male patients who met the inclusion criteria during the data collection period were vaccinated; however, six (30%) had anti-HPV at baseline, and were not considered further in the analysis. Therefore, 19 HIV-infected individuals were included in the study, along with five healthy, HPV-seronegative controls., Results: Patients infected with HIV-1 were subdivided into two groups, A and B, according to their T CD4 cells count at the time of vaccination, namely: Group A: CD4>500; Group B: CD4<500. The proportion of seroconversion after immunization with three doses of a bivalent anti-HPV vaccine was 92%., Conclusion: HIV-infected patients as well as HIV negative controls responded to anti-HPV vaccination, regardless of their T CD4 cells count and HIV plasma viral load. These results demonstrate that anti-HPV immunization in HIV-infected males is effective and should be encouraged, thus helping to decrease the risk of infection, mortality and morbidity of diseases associated with HPV in men., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Human T-cell leukemia virus type 1 (HTLV-1), hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) are prevalent worldwide, and share similar means of transmission. These infections may influence each other in evolution and outcome, including cancer or immunodeficiency. Many studies have reported the influence of genetic markers on the host immune response against different persistent viral infections, such as HTLV-1 infection, pointing to the importance of the individual genetic background on their outcomes. However, despite recent advances on the knowledge of the pathogenesis of HTLV-1 infection, gaps in the understanding of the role of the individual genetic background on the progress to disease clinically manifested still remain. In this scenario, much less is known regarding the influence of genetic factors in the context of dual or triple infections or their influence on the underlying mechanisms that lead to outcomes that differ from those observed in monoinfection. This review describes the main factors involved in the virus-host balance, especially for some particular human leukocyte antigen (HLA) haplotypes, and other important genetic markers in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other persistent viruses, such as HIV and HCV.

Human papillomavirus is one of the most common sexually transmitted diseases worldwide. The natural history of oral HPV infection is unclear, and its risk factors have not been explored. Immunocompromised individuals, as exemplified by HIV patients, are at high risk for HPV-related diseases. The mean of this study is to determine the prevalence of HPV in the oral tract of HIV-1-positive male subjects and its association with risk factors. A total of 283 oral wash samples from HIV-1-positive men were tested. The oral fluid samples were used for DNA extraction and conventional PCR amplification; HPV genotyping was performed by hybridization. HPV genotyping revealed that nine samples (3.5%) were positive for HPV DNA; the major high-risk HPV types identified were 51 and 66. Worldwide studies have shown a variable prevalence of oral HPV. The diversity of genotypes and the high prevalence of multiple infections in HIV-infected subjects can be better explained by the effects of HIV-induced immunosuppression. The most important risk factors are unprotected sexual intercourse, but other factors for this infection have been described elsewhere including smoking, age and HIV-positive serostatus. In this study, smoking was the most important risk factor for acquiring oral HPV in HIV-1-infected subjects in Brazil.

Background: The polymorphisms of IL28B have been described as important in the pathogenesis of infections caused by some viruses. The aim of this research was to evaluate whether IL28B gene polymorphisms (SNP rs8099917 and SNP rs12979860) are associated with HAM/TSP., Methods: The study included 229 subjects, classified according to their neurological status in two groups: Group I (136 asymptomatic HTLV-1 carriers) and Group II (93 HAM/TSP patients). The proviral loads were quantified, and the rs8099917 and rs12979860 SNPs in the region of IL28B-gene were analyzed by StepOnePlus Real-time PCR System., Results: A multivariate model analysis, including gender, age, and HTLV-1 DNA proviral load, showed that IL28B polymorphisms were independently associated with HAM/TSP outcome in rs12979860 genotype CT (OR = 2.03; IC95% = 0.96-4.27) and in rs8099917 genotype GG (OR = 7.61; IC95%  = 1.82-31.72)., Conclusion: Subjects with SNP rs8099917 genotype GG and rs12979618 genotype CT may present a distinct immune response against HTLV-1 infection. So, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for disease development; however, since this is the first description of such finding in the literature, we should first replicate this study with more HTLV-1-infected persons to strengthen the evidence already provided by our results.