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Pathogens
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HTLV-1 Disease
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HTLV-1 Disease

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 39914

Special Issue Editors

Dr. Fabiola Martin

E-Mail Website
Guest Editor
Faculty of Medicine and School of Public Health, University of Queensland, Brisbane 4030, Australia
Interests: HTLV; Sexual Health; HIV; HAM/TSP; ATL; Epidemiology; Systematic Reviews; Transmission Prevention Strategies; PEP; PrEP; HTLV Advocacy and Patient Representation
Dr. Chloé Journo

E-Mail Website
Guest Editor
International Center for Infectiology Research, Lyon, France
Interests: virology; cell biology; molecular biology; HTLV; oncoviruses-mediated cell transformation; cell signaling; NF-kB signaling; post-translational modifications; centrosome; protein interaction networks

Special Issue Information

Dear Colleagues,

Year 2018 was a tumultuous year for people who live with the human oncovirus, HTLV-1. Though the virus was discovered in 1980 by Robert Gallo, people have been suffering from HTLV-1 diseases for thousands of years. However, the discovery of the extraordinarily high prevalence rates as well as the associated morbidity and mortality of this blood borne and sexually transmitted virus amongst one of our culturally richest and oldest living Indigenous ancestral people shocked the scientific and general population world-wide in 2018.

As a result, for the first time in the history of HTLV-1, patient representatives, scientists and clinicians submitted the WHO HTLV-1 Open Letter to Dr.Tedros Adhanom Ghebreyesus, the director general of the World Health Organisation (WHO) to adopt HTLV as a WHO health topic, in order to work towards the eradication of HTLV-1, and to provide information, guidance and technical support to countries and communities, particularly to those most affected by the diseases.

This action resulted in a process of engaging with WHO member-states and WHO, prompting awareness that despite the significant morbidity and mortality caused by HTLV-1, many people worldwide still believe that HTLV-1 is a harmless virus. We know that about 1000 people die every year of Adult T cell Leukemia (ATL) in Japan alone. Now is the time to rephrase the problem at hand: Can one catch Adult T cell Leukemia (ATL) or HTLV-1 associated myelopathy (HAM)? Just as anal, cervical, vulval, penile and laryngeal cancers are caused through the acquisition of human papilloma virus, we believe that one can catch ATL and HAM. Therefore, we propose to consider ATL and HAM as preventable communicable diseases, caused by HTLV-1.

Pursuing research into the fundamental understanding of HTLV-1 biology is vital for the development of effective transmission prevention strategies, treatment and cure.

To this end we wish to dedicate this issue to: pathogenicity, transmission, prevention of HTLV-1.

We invite you to consider contributing to this special HTLV-1 Disease issue by focusing on biomedical discoveries made or unmet basic science needs addressing one or several of the following questions:

  • What is the evidence that HTLV-1 causes morbidity?
  • What is the evidence that HTLV-1 increases mortality?
  • How can we better equip our HTLV-1 transmission prevention and or treatment tool-box?

This special issue is an important step towards the eradication of HTLV-1 by compiling our current basic-science intervention knowledge to inform our readers as well as the participants of the WHO HTLV-1 Global Consultation, who will decide if HTLV should be adopted by the WHO as a Health Topic.

We are looking forward to hearing from you.

Dr. Fabiola Martin
Dr. Chloé Journo
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

  • Human T leukemia virus human T
  • ATL
  • lymphotropic virus
  • myelopathy
  • Tax
  • paraparesis
  • oncovirus
  • HAM/TSP
  • HBZ
  • chronic infection
  • auxiliary proteins
  • inflammation
  • cell transformation
  • immune response
  • virus-host interaction
  • mortality
  • transmission
  • vaccines
  • sexually transmitted infection
  • pre-exposure prophylaxis
  • blood-borne virus
  • post-exposure prophylaxis
  • transfusion
  • clinical trials
  • pathogenicity
  • antiretrovirals
  • leukemia
  • PrEP
  • lymphoma
  • PEP

Published Papers (10 papers)

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Editorial

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3 pages, 207 KiB  
Editorial
HTLV-1 Disease
by Chloé Journo and Fabiola Martin
Pathogens 2021, 10(8), 1001; https://doi.org/10.3390/pathogens10081001 - 09 Aug 2021
Cited by 2 | Viewed by 1680
Abstract
The years 2020 and 2021 will remain memorable years for many reasons [...] Full article
(This article belongs to the Special Issue HTLV-1 Disease)
4 pages, 177 KiB  
Editorial
Human T leukaemia Type 1 and COVID-19
by Abelardo Araujo and Fabiola Martin
Pathogens 2020, 9(6), 438; https://doi.org/10.3390/pathogens9060438 - 03 Jun 2020
Cited by 8 | Viewed by 2812
Abstract
In the absence of clinical data on Human T leukaemia Type 1 and COVID-19 infection, we are providing guidance to clinicians who look after people living with HTLV-1. Full article
(This article belongs to the Special Issue HTLV-1 Disease)

Research

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11 pages, 1527 KiB  
Article
Early-Onset HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis
by Alvaro Schwalb, Valeria Pérez-Muto, Rodrigo Cachay, Martín Tipismana, Carolina Álvarez, Fernando Mejía, Elsa González-Lagos and Eduardo Gotuzzo
Pathogens 2020, 9(6), 450; https://doi.org/10.3390/pathogens9060450 - 07 Jun 2020
Cited by 9 | Viewed by 2560
Abstract
Background: Vertical transmission of HTLV-1 could lead to the early development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This significantly affects quality of life and increases morbimortality. Objective: To describe the epidemiological and clinical characteristics of patients with early-onset HAM/TSP, defined as disease onset [...] Read more.
Background: Vertical transmission of HTLV-1 could lead to the early development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This significantly affects quality of life and increases morbimortality. Objective: To describe the epidemiological and clinical characteristics of patients with early-onset HAM/TSP, defined as disease onset before 20 years of age. Methods: This is a retrospective study from an HTLV-1 clinical cohort between 1989 and 2019. We searched for medical records of patients with (1) diagnosis of HTLV-1 infection using two ELISA and/or one Western blot, (2) clinical diagnosis of HAM/TSP by neurological assessment, and (3) HAM/TSP symptom-onset before 20 years of age. Results: A total of 38 cases were identified in the cohort; 25 were female (66%). The median age of onset was 14 years old. 31 (82%) cases had HTLV-1 testing done among family members; 22 out of 25 tested mothers (88%) were HTLV-1 positive. Most patients (27/34) were breastfed for more than one year. Disease progression measured through EDSS and IPEC-1 showed an upward trend towards worsening spasticity with 18 patients (47%) eventually requiring mobility aids. Conclusions: Cases of early-onset HAM/TSP are not of rare occurrence, which translates into many more years of dependency, the use of mobility aids, and increased overall morbidity. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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10 pages, 957 KiB  
Article
Dichotomy in Fatal Outcomes in a Large Cohort of People Living with HTLV-1 in São Paulo, Brazil
by Rosa Maria N. Marcusso, Johan Van Weyenbergh, João Victor Luisi de Moura, Flávia Esper Dahy, Aline de Moura Brasil Matos, Michel E. J. Haziot, Jose E. Vidal, Luiz Augusto M. Fonseca, Jerusa Smid, Tatiane Assone, Jorge Casseb and Augusto César Penalva de Oliveira
Pathogens 2020, 9(1), 25; https://doi.org/10.3390/pathogens9010025 - 26 Dec 2019
Cited by 14 | Viewed by 2976
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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Review

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22 pages, 806 KiB  
Review
Human T-cell Leukemia Virus Type 1 and Strongyloides stercoralis: Partners in Pathogenesis
by Adam Dykie, Tharaka Wijesinghe, Arnold B. Rabson, Kiran Madugula, Christian Farinas, Sydney Wilson, David Abraham and Pooja Jain
Pathogens 2020, 9(11), 904; https://doi.org/10.3390/pathogens9110904 - 29 Oct 2020
Cited by 17 | Viewed by 3983
Abstract
Infection with human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has been associated with various clinical syndromes including co-infection with Strongyloides stercoralis, which is an intestinal parasitic nematode and the leading cause of strongyloidiasis in humans. Interestingly, HTLV-1 endemic areas coincide with regions [...] Read more.
Infection with human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has been associated with various clinical syndromes including co-infection with Strongyloides stercoralis, which is an intestinal parasitic nematode and the leading cause of strongyloidiasis in humans. Interestingly, HTLV-1 endemic areas coincide with regions citing high prevalence of S. stercoralis infection, making these communities optimal for elucidating the pathogenesis of co-infection and its clinical significance. HTLV-1 co-infection with S. stercoralis has been observed for decades in a number of published patient cases and case series; however, the implications of this co-infection remain elusive. Thus far, data suggest that S. stercoralis increases proviral load in patients co-infected with HTLV-1 compared to HTLV-1 infection alone. Furthermore, co-infection with HTLV-1 has been associated with shifting the immune response from Th2 to Th1, affecting the ability of the immune system to address the helminth infection. Thus, despite this well-known association, further research is required to fully elucidate the impact of each pathogen on disease manifestations in co-infected patients. This review provides an analytical view of studies that have evaluated the variation within HTLV-1 patients in susceptibility to S. stercoralis infection, as well as the effects of strongyloidiasis on HTLV-1 pathogenesis. Further, it provides a compilation of available clinical reports on the epidemiology and pathology of HTLV-1 with parasitic co-infection as well as data from mechanistic studies suggesting possible immunopathogenic mechanisms. Furthermore, specific areas of potential future research have been highlighted to facilitate advancing understanding of the complex interactions between these two pathogens. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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28 pages, 2026 KiB  
Review
Mechanisms of Oncogenesis by HTLV-1 Tax
by Suchitra Mohanty and Edward W. Harhaj
Pathogens 2020, 9(7), 543; https://doi.org/10.3390/pathogens9070543 - 07 Jul 2020
Cited by 53 | Viewed by 8784
Abstract
The human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), a neoplasm of CD4+CD25+ T cells that occurs in 2–5% of infected individuals after decades of asymptomatic latent infection. Multiple HTLV-1-encoded regulatory proteins, including Tax and [...] Read more.
The human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), a neoplasm of CD4+CD25+ T cells that occurs in 2–5% of infected individuals after decades of asymptomatic latent infection. Multiple HTLV-1-encoded regulatory proteins, including Tax and HTLV-1 basic leucine zipper factor (HBZ), play key roles in viral persistence and latency. The HTLV-1 Tax oncoprotein interacts with a plethora of host cellular proteins to regulate viral gene expression and also promote the aberrant activation of signaling pathways such as NF-κB to drive clonal proliferation and survival of T cells bearing the HTLV-1 provirus. Tax undergoes various post-translational modifications such as phosphorylation and ubiquitination that regulate its function and subcellular localization. Tax shuttles in different subcellular compartments for the activation of anti-apoptotic genes and deregulates the cell cycle with the induction of DNA damage for the accumulation of genomic instability that can result in cellular immortalization and malignant transformation. However, Tax is highly immunogenic and therefore HTLV-1 has evolved numerous strategies to tightly regulate Tax expression while maintaining the pool of anti-apoptotic genes through HBZ. In this review, we summarize the key findings on the oncogenic mechanisms used by Tax that set the stage for the development of ATLL, and the strategies used by HTLV-1 to tightly regulate Tax expression for immune evasion and viral persistence. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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14 pages, 715 KiB  
Review
Antiretroviral Therapy in HTLV-1 Infection: An Updated Overview
by Francesca Marino-Merlo, Emanuela Balestrieri, Claudia Matteucci, Antonio Mastino, Sandro Grelli and Beatrice Macchi
Pathogens 2020, 9(5), 342; https://doi.org/10.3390/pathogens9050342 - 01 May 2020
Cited by 25 | Viewed by 4084
Abstract
The human T cell leukemic/lymphotropic virus type 1 (HTLV-1), discovered several years ago, is the causative agent for a rapid progressive haematological malignancy, adult T cell leukemia (ATL), for debilitating neurological diseases and for a number of inflammatory based diseases. Although the heterogeneous [...] Read more.
The human T cell leukemic/lymphotropic virus type 1 (HTLV-1), discovered several years ago, is the causative agent for a rapid progressive haematological malignancy, adult T cell leukemia (ATL), for debilitating neurological diseases and for a number of inflammatory based diseases. Although the heterogeneous features of the diseases caused by HTLV-1, a common topic concerning related therapeutic treatments relies on the use of antiretrovirals. This review will compare the different approaches and opinions in this matter, giving a concise overview of preclinical as well as clinical studies covering all the aspects of antiretrovirals in HTLV-1 infection. Studies will be grouped on the basis of the class of antiretroviral, putting together both pre-clinical and clinical results and generally following a chronological order. Analysis of the existing literature highlights that a number of preclinical studies clearly demonstrate that different classes of antiretrovirals, already utilized as anti-HIV agents, are actually capable to efficiently contrast HTLV-1 infection. Nevertheless, the results of most of the clinical studies are generally discouraging on the same point. In conclusion, the design of new antiretrovirals more specifically focused on HTLV-1 targets, and/or the establishment of early treatments with antiretrovirals could hopefully change the perspectives of diseases caused by HTLV-1. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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20 pages, 1693 KiB  
Review
The Complex Relationship between HTLV-1 and Nonsense-Mediated mRNA Decay (NMD)
by Léa Prochasson, Pierre Jalinot and Vincent Mocquet
Pathogens 2020, 9(4), 287; https://doi.org/10.3390/pathogens9040287 - 15 Apr 2020
Cited by 6 | Viewed by 3099
Abstract
Before the establishment of an adaptive immune response, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these [...] Read more.
Before the establishment of an adaptive immune response, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defense mechanisms are debated. Among these mechanisms, we focused on an RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as has been recently demonstrated. NMD is a co-translational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition. HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the fittest clones despite genome instability; however, its direct long-term impact remains to be investigated. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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11 pages, 272 KiB  
Review
Neurological Aspects of HIV-1/HTLV-1 and HIV-1/HTLV-2 Coinfection
by Abelardo Q.-C. Araujo
Pathogens 2020, 9(4), 250; https://doi.org/10.3390/pathogens9040250 - 28 Mar 2020
Cited by 11 | Viewed by 3087
Abstract
Simultaneous infection by human immunodeficiency viruses (HIV) and human T-lymphotropic viruses (HTLV) are not uncommon since they have similar means of transmission and are simultaneously endemic in many populations. Besides causing severe immune dysfunction, these viruses are neuropathogenic and can cause neurological diseases [...] Read more.
Simultaneous infection by human immunodeficiency viruses (HIV) and human T-lymphotropic viruses (HTLV) are not uncommon since they have similar means of transmission and are simultaneously endemic in many populations. Besides causing severe immune dysfunction, these viruses are neuropathogenic and can cause neurological diseases through direct and indirect mechanisms. Many pieces of evidence at present show that coinfection may alter the natural history of general and, more specifically, neurological disorders through different mechanisms. In this review, we summarize the current evidence on the influence of coinfection on the progression and outcome of neurological complications of HTLV-1/2 and HIV-1. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
18 pages, 1256 KiB  
Review
NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ
by Stefania Fochi, Vincenzo Ciminale, Elisabetta Trabetti, Umberto Bertazzoni, Donna M. D’Agostino, Donato Zipeto and Maria Grazia Romanelli
Pathogens 2019, 8(4), 290; https://doi.org/10.3390/pathogens8040290 - 10 Dec 2019
Cited by 19 | Viewed by 4535
Abstract
The risk of developing adult T-cell leukemia/lymphoma (ATLL) in individuals infected with human T-cell lymphotropic virus 1 (HTLV-1) is about 3–5%. The mechanisms by which the virus triggers this aggressive cancer are still an area of intensive investigation. The viral protein Tax-1, together [...] Read more.
The risk of developing adult T-cell leukemia/lymphoma (ATLL) in individuals infected with human T-cell lymphotropic virus 1 (HTLV-1) is about 3–5%. The mechanisms by which the virus triggers this aggressive cancer are still an area of intensive investigation. The viral protein Tax-1, together with additional regulatory proteins, in particular HTLV-1 basic leucine zipper factor (HBZ), are recognized as relevant viral factors required for both viral replication and transformation of infected cells. Tax-1 deregulates several cellular pathways affecting the cell cycle, survival, and proliferation. The effects of Tax-1 on the NF-κB pathway have been thoroughly studied. Recent studies also revealed the impact of Tax-1 and HBZ on microRNA expression. In this review, we summarize the recent progress in understanding the contribution of HTLV-1 Tax- and HBZ-mediated deregulation of NF-κB and the microRNA regulatory network to HTLV-1 pathogenesis. Full article
(This article belongs to the Special Issue HTLV-1 Disease)
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