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Pathogens
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New Directions in HTLV-1 Research
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New Directions in HTLV-1 Research

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 12484

Special Issue Editors

Dr. Arnold B. Rabson

E-Mail Website
Guest Editor
Child Health Institute of New Jersey and Departments of Pharmacology, Pediatrics and Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
Interests: human retroviral infections; HTLV-1; HIV; gene regulation
Dr. Steven Jacobson

E-Mail Website
Guest Editor
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Interests: HTLV-1; viral immunology; neurology

Special Issue Information

Dear Colleagues,

Since its initial discovery in 1981 as the causative agent of Adult T Cell Leukemia/Lymphoma (ATL, ATLL), the range of outcomes associated with infection with the human T cell leukemia virus type 1 (HTLV-1) has expanded remarkably. The discovery, five years later, of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) expanded our vision of this virus and its capabilities to include a widening array of inflammatory and immune-related disorders. Although the majority of infected individuals do not develop direct HTLV-1 associated pathologies, infection with HTLV-1 may also enhance the incidence and severity of other infections and other chronic, inflammatory diseases. Furthermore, new endemic foci continue to be identified and novel treatment modalities for refractory HTLV-1 diseases continue to be developed.  

This volume seeks to address fundamental questions in HTLV-1 pathogenesis that remain unresolved even 50 years after its initial discovery. Since the successful first volume in Pathogens of “HTLV-1 Disease”, edited by Fabiola Martin and Chloé Journo in 2020, new technologies and model systems have further interrogated different aspects of HTLV-1 infection and pathogenesis, further intensifying interest in mechanisms of HTLV-1 pathogenesis and novel approaches to treatment and prevention. Among the many outstanding questions, most intriguingly is how infection can, with a single, relatively simple virus, lead to such dramatically different outcomes in infected individuals? What are molecular aspects of HTLV-1 infection that changes their properties and functions of infected cells, and how do these effects contribute to diseases? What are the characteristics of host immune response to HTLV infection and how do these affect viral dynamics and disease pathogenesis? Are there animal models that can help to elucidate these complex pathogenic pathways? How have rapidly evolving technologies, such as multi-omic approaches, contributed to our understanding of HTLV-1- associated diseases? Are there potential markers to identify infected persons at risk for the different disease phenotypes? What are the newest treatment opportunities and can these affect not only symptoms and disease progression, but also the quality of life for infected people in different societies around the globe? 

With the recent upsurge in global awareness of HTLV-1 infection, as represented by the adoption of HTLV-1 as a health topic of the World Health Organization, and building on the momentum that will be generated by the upcoming international conference, HTLV22, this volume represents an opportune moment to reassess fundamental concepts HTLV-1 disease pathogenesis, treatment, and prevention. 

We invite you to contribute to this exciting project.

Dr. Arnold B. Rabson
Dr. Steven Jacobson
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • retrovirus
  • oncogenesis
  • pathogenesis
  • bovine leukemia virus
  • adult T cell leukemia/lymphoma
  • ATL
  • lymphoma
  • leukemia
  • HTLV-associated myelopathy/tropical spastic paraparesis
  • HAM/TSP
  • myelopathy
  • paraparesis
  • uveitis
  • infective dermatitis
  • inflammation

Published Papers (8 papers)

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Research

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23 pages, 3559 KiB  
Article
Complete Rescue of HTLV-1p12KO Infectivity by Depletion of Monocytes Together with NK and CD8+ T Cells
by Anna Gutowska, Sarkis Sarkis, Mohammad Arif Rahman, Katherine C. Goldfarbmuren, Ramona Moles, Massimiliano Bissa, Melvin Doster, Robyn Washington-Parks, Katherine McKinnon, Isabela Silva de Castro, Luca Schifanella, Genoveffa Franchini and Cynthia A. Pise-Masison
Pathogens 2024, 13(4), 292; https://doi.org/10.3390/pathogens13040292 - 29 Mar 2024
Viewed by 1064
Abstract
The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These [...] Read more.
The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1WT (wild type) and HTLV-1p12KO (Orf-1 knockout) infectivity, but seroconversion to either virus is not sustained over time, suggesting a progressive decrease in virus expression. These results raise the hypotheses that either HTLV-1 persistence depends on a monocyte reservoir or monocyte depletion provides a transient immune evasion benefit. To test these hypotheses, we simultaneously depleted NK cells, CD8+ T cells, and monocytes (triple depletion) prior to exposure to HTLV-1WT or HTLV-1p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1p12KO infectivity. Following triple depletion, we observed rapid and sustained seroconversion, high titers of antibodies against HTLV-1 p24Gag, and frequent detection of viral DNA in the blood and tissues of all animals when compared with depletion of only CD8+ and NK cells, or monocytes alone. The infection of macaques with HTLV-1WT or HTLV-1p12KO was associated with higher plasma levels of IL-10 after 21 weeks, while IL-6, IFN-γ, IL-18, and IL-1β were only elevated in animals infected with HTLV-1WT. The repeat depletion of monocytes, NK, and CD8+ cells seven months following the first exposure to HTLV-1 did not further exacerbate viral replication. These results underscore the contribution of monocytes in orchestrating anti-viral immunity. Indeed, the absence of orf-1 expression was fully compensated by the simultaneous depletion of CD8+ T cells, NK cells, and monocytes, underlining the primary role of orf-1 in hijacking host immunity. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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12 pages, 728 KiB  
Article
Socio-Demographic, Clinical, and Mortality Differences between HIV-Infected and HIV/HTLV-1 Co-Infected Patients in Peru
by Maria Pia Amanzo-Vargas, Tessy Arellano-Veintemilla, Elsa González-Lagos, Juan Echevarría, Fernando Mejía, Ana Graña and Eduardo Gotuzzo
Pathogens 2023, 12(7), 869; https://doi.org/10.3390/pathogens12070869 - 24 Jun 2023
Viewed by 953
Abstract
Background and aims: In Peru, the estimated prevalence of human immunodeficiency virus (HIV) and human T-lymphotropic virus-1 (HTLV-1) co-infection has been reported to be as high as 18%. Despite the endemicity of HTLV-1 in Peru, few studies have assessed the impact of HIV/HTLV-1 [...] Read more.
Background and aims: In Peru, the estimated prevalence of human immunodeficiency virus (HIV) and human T-lymphotropic virus-1 (HTLV-1) co-infection has been reported to be as high as 18%. Despite the endemicity of HTLV-1 in Peru, few studies have assessed the impact of HIV/HTLV-1 co-infection. Our study compared socio-demographic and clinical characteristics, and mortality rates between HIV-infected and HIV/HTLV-1 co-infected patients. Methods: We reviewed the medical records of patients aged 18 years and older belonging to the HIV and HTLV-1 cohorts in Lima during a 30-year period: 1989–2019. Each HIV/HTLV-1 co-infected patient was randomly matched with two HIV-infected patients with similar characteristics (same sex, age ± 5 years, and same year of HIV diagnosis). Allegedly co-infected patients without a confirmatory diagnosis of HIV and HTLV-1 were excluded. Most of the patients in the HIV-infected group did not have a negative test result for HTLV-1 infection, so we used two probabilistic sensitivity analysis models to correct for potential HTLV-1 exposure misclassification bias in the group of HIV-infected patients. Results: Of 162 patients enrolled, 54 were HIV/HTLV-1 co-infected and 108 were HIV-infected. The median age was 42 years (IQR = 34–51 years) and the majority were male (61.1%), single (44.4%), heterosexual (71%), born in Lima (58%), educated at the secondary school level (55.6%), and receiving antiretroviral treatment (91.4%). HIV/HTLV-1 co-infection was associated with an increased risk of death (HR: 11.8; 95% CI: 1.55–89.00; p = 0.017) while antiretroviral treatment was associated with a decreased risk of death (HR: 0.03; 95% CI: 0.003–0.25; p = 0.001). The overall mortality rate was 13.6 per 100 persons and the survival time for co-infected patients (median = 14.19 years) was significantly shorter than that of HIV-infected patients (median = 23.83 years) (p < 0.001). Conclusions: HIV/HTLV-1 co-infected patients had a significantly shorter survival time compared to HIV-infected patients, suggesting that the immune alterations caused by HTLV-1 in CD4 cell count may have contributed to late initiation of antiretroviral treatment and prophylaxis against opportunistic infections over the decades, and thus reducing their benefits in these patients. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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21 pages, 2459 KiB  
Article
Upregulation of Neuropilin-1 Inhibits HTLV-1 Infection
by Wesley Kendle, Kimson Hoang, Erica Korleski, Amanda R. Panfil, Nicholas Polakowski and Isabelle Lemasson
Pathogens 2023, 12(6), 831; https://doi.org/10.3390/pathogens12060831 - 15 Jun 2023
Viewed by 1319
Abstract
Infection with human T-cell leukemia virus type 1 (HTLV-1) can produce a spectrum of pathological effects ranging from inflammatory disorders to leukemia. In vivo, HTLV-1 predominantly infects CD4+ T-cells. Infectious spread within this population involves the transfer of HTLV-1 virus particles from [...] Read more.
Infection with human T-cell leukemia virus type 1 (HTLV-1) can produce a spectrum of pathological effects ranging from inflammatory disorders to leukemia. In vivo, HTLV-1 predominantly infects CD4+ T-cells. Infectious spread within this population involves the transfer of HTLV-1 virus particles from infected cells to target cells only upon cell-to-cell contact. The viral protein, HBZ, was found to enhance HTLV-1 infection through transcriptional activation of ICAM1 and MYOF, two genes that facilitate viral infection. In this study, we found that HBZ upregulates the transcription of COL4A1, GEM, and NRP1. COL4A1 and GEM are genes involved in viral infection, while NRP1, which encodes neuropilin 1 (Nrp1), serves as an HTLV-1 receptor on target cells but has no reported function on HTLV-1-infected cells. With a focus on Nrp1, cumulative results from chromatin immunoprecipitation assays and analyses of HBZ mutants support a model in which HBZ upregulates NRP1 transcription by augmenting recruitment of Jun proteins to an enhancer downstream of the gene. Results from in vitro infection assays demonstrate that Nrp1 expressed on HTLV-1-infected cells inhibits viral infection. Nrp1 was found to be incorporated into HTLV-1 virions, and deletion of its ectodomain removed the inhibitory effect. These results suggest that inhibition of HTLV-1 infection by Nrp1 is caused by the ectodomain of Nrp1 extended from virus particles, which may inhibit the binding of virus particles to target cells. While HBZ has been found to enhance HTLV-1 infection using cell-based models, there may be certain circumstances in which activation of Nrp1 expression negatively impacts viral infection, which is discussed. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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9 pages, 605 KiB  
Article
Iliopsoas Muscle Weakness as a Key Diagnostic Marker in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)
by Eiji Matsuura, Satoshi Nozuma, Mika Dozono, Daisuke Kodama, Masakazu Tanaka, Ryuji Kubota and Hiroshi Takashima
Pathogens 2023, 12(4), 592; https://doi.org/10.3390/pathogens12040592 - 13 Apr 2023
Cited by 1 | Viewed by 1378
Abstract
Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, [...] Read more.
Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, HAM/TSP, are empirically known to include weakness of the proximal muscles of the lower extremities and atrophy of the paraspinal muscles, which is characteristic of the distribution of disturbed muscles usually seen in muscular diseases, except that the upper extremities are almost normal. This unique clinical presentation is useful information for physicians and physical therapists involved in diagnosing and rehabilitating patients with HAM/TSP, as well as critical information for understanding the pathogenesis of HAM/TSP. However, the precise pattern of muscle involvement in this condition has yet to be reported. The purpose of this study was to identify the muscles affected by HAM/TSP in order to understand the pathogenesis of HAM/TSP as well as to aid in the diagnosis and rehabilitation of HAM/TSP. A retrospective review of medical records was conducted on 101 consecutively admitted patients with HAM/TSP at Kagoshima University Hospital. Among 101 patients with HAM/TSP, all but three had muscle weakness in the lower extremities. Specifically, the hamstrings and iliopsoas muscle were the most frequently affected in over 90% of the patients. Manual muscle testing (MMT) revealed that the iliopsoas was the weakest of the muscles assessed, a consistent feature from the early to advanced stages of the disease. Our findings demonstrate a unique distribution of muscle weakness in HAM/TSP, with the proximal muscles of the lower extremities, particularly the iliopsoas muscle, being the most frequently and severely affected. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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10 pages, 305 KiB  
Article
COVID-19 among People Living with HTLV-1 Infection in Rio de Janeiro, Brazil
by Marzia Puccioni-Sohler, Alana Cristina Jasset Miranda, Cíntia da Silva Mello, Stéphanie Monnerat Magalhães, Luciane Cardoso dos Santos Rodrigues and Dario J. H. P. Signorini
Pathogens 2023, 12(2), 242; https://doi.org/10.3390/pathogens12020242 - 03 Feb 2023
Cited by 1 | Viewed by 2314
Abstract
The impact of coronavirus disease 2019 (COVID-19) on people living with human T-cell leukemia virus type 1 (HTLV-1) is unknown. The aim of this study is to evaluate the COVID-19 risk factors and outcomes of HTLV-1-infected individuals. A retrospective study of seropositive HTLV-1 [...] Read more.
The impact of coronavirus disease 2019 (COVID-19) on people living with human T-cell leukemia virus type 1 (HTLV-1) is unknown. The aim of this study is to evaluate the COVID-19 risk factors and outcomes of HTLV-1-infected individuals. A retrospective study of seropositive HTLV-1 outpatients seen during the COVID-19 pandemic period (2020–2022) was conducted in a Tertiary Hospital in Rio de Janeiro, Brazil. We compared the demographic and comorbidity/risk factors in patients with COVID-19 and non-COVID-19 diagnoses. In addition, the clinical features of COVID-19 and vaccination status were also investigated in 51 HTLV-1-infected individuals. The majority (88.2%) had COVID-19 comorbidity/risk factors. Seven cases were vaccinated against COVID-19. Overall, 19 out of 51 (37.3%) individuals were diagnosed with COVID-19. We found differences only in the frequency of anxiety in both groups: 57.9% in the COVID-19 group vs. 15.6% in the non-COVID-19 (p < 0.05) group. Thirteen out of nineteen (68%) of the COVID-19 cases progressed to mild/moderate illness, one remained asymptomatic, and 26.3% progressed to severe illness. All of the individuals recovered at home, but the majority (57.9%) developed post-COVID-19 symptoms: anosmia and ageusia (31.6%), worsening anxiety (15.8%), and a feeling of pain in the legs (15.8%). The patients with post-COVID-19 conditions were unvaccinated. Our findings show that HTLV-1 did not increase the risk of lethal COVID-19 and underline the importance of promoting mental health in HTLV-1-infected individuals. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)

Review

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17 pages, 14185 KiB  
Review
HTLV-1 Tax Tug-of-War: Cellular Senescence and Death or Cellular Transformation
by Marcia Bellon and Christophe Nicot
Pathogens 2024, 13(1), 87; https://doi.org/10.3390/pathogens13010087 - 19 Jan 2024
Viewed by 1096
Abstract
Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with a lymphoproliferative disease known as adult T cell leukemia/lymphoma (ATLL). HTLV-1 infection efficiently transforms human T cells in vivo and in vitro. The virus does not transduce a proto-oncogene, nor [...] Read more.
Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with a lymphoproliferative disease known as adult T cell leukemia/lymphoma (ATLL). HTLV-1 infection efficiently transforms human T cells in vivo and in vitro. The virus does not transduce a proto-oncogene, nor does it integrate into tumor-promoting genomic sites. Instead, HTLV-1 uses a random mutagenesis model, resulting in cellular transformation. Expression of the viral protein Tax is critical for the immortalization of infected cells by targeting specific cellular signaling pathways. However, Tax is highly immunogenic and represents the main target for the elimination of virally infected cells by host cytotoxic T cells (CTLs). In addition, Tax expression in naïve cells induces pro-apoptotic signals and has been associated with the induction of non-replicative cellular senescence. This review will explore these conundrums and discuss the mechanisms used by the Tax viral oncoprotein to influence life-and-death cellular decisions and affect HTLV-1 pathogenesis. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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24 pages, 1011 KiB  
Review
Antibody and Cell-Based Therapies against Virus-Induced Cancers in the Context of HIV/AIDS
by Julie Joseph, Grace Sandel, Ratuja Kulkarni, Reem Alatrash, Bobby Brooke Herrera and Pooja Jain
Pathogens 2024, 13(1), 14; https://doi.org/10.3390/pathogens13010014 - 22 Dec 2023
Viewed by 1585
Abstract
Infectious agents, notably viruses, can cause or increase the risk of cancer occurrences. These agents often disrupt normal cellular functions, promote uncontrolled proliferation and growth, and trigger chronic inflammation, leading to cancer. Approximately 20% of all cancer cases in humans are associated with [...] Read more.
Infectious agents, notably viruses, can cause or increase the risk of cancer occurrences. These agents often disrupt normal cellular functions, promote uncontrolled proliferation and growth, and trigger chronic inflammation, leading to cancer. Approximately 20% of all cancer cases in humans are associated with an infectious pathogen. The International Agency for Research on Cancer (IARC) recognizes seven viruses as direct oncogenic agents, including Epstein–Barr Virus (EBV), Kaposi’s Sarcoma-associated herpesvirus (KSHV), human T-cell leukemia virus type-1 (HTLV-1), human papilloma virus (HPV), hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1). Most viruses linked to increased cancer risk are typically transmitted through contact with contaminated body fluids and high-risk behaviors. The risk of infection can be reduced through vaccinations and routine testing, as well as recognizing and addressing risky behaviors and staying informed about public health concerns. Numerous strategies are currently in pre-clinical phases or undergoing clinical trials for targeting cancers driven by viral infections. Herein, we provide an overview of risk factors associated with increased cancer incidence in people living with HIV (PLWH) as well as other chronic viral infections, and contributing factors such as aging, toxicity from ART, coinfections, and comorbidities. Furthermore, we highlight both antibody- and cell-based strategies directed against virus-induced cancers while also emphasizing approaches aimed at discovering cures or achieving complete remission for affected individuals. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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12 pages, 1225 KiB  
Review
HAM/TSP Pathogenesis: The Transmigration Activity of HTLV-1-Infected T Cells into Tissues
by Tatsufumi Nakamura
Pathogens 2023, 12(3), 492; https://doi.org/10.3390/pathogens12030492 - 21 Mar 2023
Cited by 1 | Viewed by 1697
Abstract
Slowly progressive spastic paraparesis with bladder dysfunction, the main clinical feature of human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction [...] Read more.
Slowly progressive spastic paraparesis with bladder dysfunction, the main clinical feature of human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by inflammatory cytokines, etc., induced under the interaction between infiltrated HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ cytotoxic T cells, has been considered implicated for the induction of chronic inflammation. As this bystander mechanism is triggered conceivably by the transmigration of HTLV-1-infected CD4+ T cells to the spinal cord, heightened transmigrating activity of HTLV-1-infected CD4+ T cells to the spinal cord might play a crucial role as the first responder in the development of HAM/TSP. This review evaluated the functions of HTLV-1-infected CD4+ T cells in HAM/TSP patients as the prerequisite for the acquisition of the activity such as adhesion molecule expression changes, small GTPases activation, and expression of mediators involved in basement membrane disruption. The findings suggest that HTLV-1-infected CD4+ T cells in HAM/TSP patients have enough potential to facilitate transmigration into the tissues. Future HAM/TSP research should clarify the molecular mechanisms leading to the establishment of HTLV-1-infected CD4+ T cells as the first responder in HAM/TSP patients. In addition, a regimen with an inhibitory activity against the transmigration of HTLV-1-infected CD4+ T cells into the spinal cord might be recommended as one of the therapeutic strategies against HAM/TSP patients. Full article
(This article belongs to the Special Issue New Directions in HTLV-1 Research)
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