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Viruses
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HTLV-1 and HTLV-1-Associated Diseases
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HTLV-1 and HTLV-1-Associated Diseases

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 19214

Special Issue Editor

Dr. Takuya Fukushima

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Guest Editor
Laboratory of Hematoimmunology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus 207 Uehara, Nishihara, Okinawa 903-0215, Japan
Interests: epidemiology; infection prevention; neutralizing antibodies; oncogenesis; biomarkers; clinical trials

Special Issue Information

Dear Colleagues,

Human T-cell leukemia virus type-I (HTLV-1) is the retrovirus that causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM), which are a refractory hematologic malignancy and neuroinflammatory disease, respectively. HTLV-1 is endemic in southwestern Japan, Sub-Saharan Africa, South America, the Caribbean islands, and parts of the Middle East and Australo-Melanesia, and the number of HTLV-1 carriers worldwide was estimated to be about 10 million in 2012. However, there is no vaccine against HTLV-1 infection and no effective drugs for curing ATL and HAM. Among the array of viral factors and host T-cell signaling pathways, Tax and HBZ are known to play major roles in the leukemogenesis of HTLV-1-infected cells in ATL, but the precise mechanisms underlying the pathogenesis of ATL and HAM remain to be fully elucidated in order to develop new molecular targeted agents. Eradicating HTLV-1 requires continued worldwide epidemiological surveys of the actual situation of HTLV-1 infections and infection prevention measures, especially for mother-to-child transmission. Moreover, the development of an HTLV-1 vaccine and the discovery of new diagnostic markers for ATL are essential.

This Special Issue will focus on the prevention of HTLV-1 infections, and the pathogenesis, diagnosis, and treatment of ATL and other HTLV-1-associated diseases.

Dr. Takuya Fukushima
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 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

  • HTLV-1
  • ATL
  • HAM
  • epidemiology
  • infection prevention
  • vaccine
  • diagnosis
  • ATL marker
  • pathogenesis
  • other HTLV-1-associated diseases

Published Papers (7 papers)

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Research

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10 pages, 1451 KiB  
Article
Elevation of the Plasma Levels of TNF Receptor 2 in Association with Those of CD25, OX40, and IL-10 and HTLV-1 Proviral Load in Acute Adult T-Cell Leukemia
by Megumi Kato, Naoki Imaizumi, Reiko Tanaka, Mariko Mizuguchi, Masaki Hayashi, Takashi Miyagi, Junnosuke Uchihara, Kazuiku Ohshiro, Junpei Todoroki, Kennosuke Karube, Hiroaki Masuzaki, Yuetsu Tanaka and Takuya Fukushima
Viruses 2022, 14(4), 751; https://doi.org/10.3390/v14040751 - 03 Apr 2022
Cited by 2 | Viewed by 2324
Abstract
Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be [...] Read more.
Adult T-cell leukemia/lymphoma (ATL) cells express TNF receptor type-2 (TNFR2) on their surface and shed its soluble form (sTNFR2). We previously reported that sTNFR2 levels were highly elevated in the plasma of patients with acute ATL. To investigate whether its quantitation would be helpful for the diagnosis or prediction of the onset of acute ATL, we examined the plasma levels of sTNFR2 in a large number of specimens obtained from a cohort of ATL patients and asymptomatic human T-cell leukemia virus type 1 (HTLV-1) carriers (ACs) and compared them to those of other candidate ATL biomarkers (sCD25, sOX40, and IL-10) by enzyme-linked immunosorbent assays (ELISA) and HTLV-1 proviral loads. We observed that sTNFR2 levels were significantly elevated in acute ATL patients compared to ACs and patients with other types of ATL (chronic, smoldering, and lymphoma). Importantly, sTNFR2 levels were significantly correlated with those of sCD25, sOX40, and IL-10, as well as proviral loads. Thus, the present study confirmed that an increase in plasma sTNFR2 levels is a biomarker for the diagnosis of acute ATL. Examination of plasma sTNFR2 alone or in combination with other ATL biomarkers may be helpful for the diagnosis of acute ATL. Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
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15 pages, 1014 KiB  
Article
Cytolytic Recombinant Vesicular Stomatitis Viruses Expressing STLV-1 Receptor Specifically Eliminate STLV-1 Env-Expressing Cells in an HTLV-1 Surrogate Model In Vitro
by Yohei Seki, Tomoya Kitamura, Kenta Tezuka, Megumi Murata, Hirofumi Akari, Isao Hamaguchi and Kazu Okuma
Viruses 2022, 14(4), 740; https://doi.org/10.3390/v14040740 - 31 Mar 2022
Viewed by 2036
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) causes serious and intractable diseases in some carriers after infection. The elimination of infected cells is considered important to prevent this onset, but there are currently no means by which to accomplish this. We previously developed [...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1) causes serious and intractable diseases in some carriers after infection. The elimination of infected cells is considered important to prevent this onset, but there are currently no means by which to accomplish this. We previously developed “virotherapy”, a therapeutic method that targets and kills HTLV-1-infected cells using a cytolytic recombinant vesicular stomatitis virus (rVSV). Infection with rVSV expressing an HTLV-1 primary receptor elicits therapeutic effects on HTLV-1-infected envelope protein (Env)-expressing cells in vitro and in vivo. Simian T-cell leukemia virus type 1 (STLV-1) is closely related genetically to HTLV-1, and STLV-1-infected Japanese macaques (JMs) are considered a useful HTLV-1 surrogate, non-human primate model in vivo. Here, we performed an in vitro drug evaluation of rVSVs against STLV-1 as a preclinical study. We generated novel rVSVs encoding the STLV-1 primary receptor, simian glucose transporter 1 (JM GLUT1), with or without an AcGFP reporter gene. Our data demonstrate that these rVSVs specifically and efficiently infected/eliminated the STLV-1 Env-expressing cells in vitro. These results indicate that rVSVs carrying the STLV-1 receptor could be an excellent candidate for unique anti-STLV-1 virotherapy; therefore, such antivirals can now be applied to STLV-1-infected JMs to determine their therapeutic usefulness in vivo. Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
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9 pages, 700 KiB  
Article
Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma
by Takuro Kameda, Kotaro Shide, Yuki Tahira, Masaaki Sekine, Seiichi Sato, Junzo Ishizaki, Masanori Takeuchi, Keiichi Akizuki, Ayako Kamiunten, Haruko Shimoda, Takanori Toyama, Kouichi Maeda, Kiyoshi Yamashita, Noriaki Kawano, Hiroshi Kawano, Tomonori Hidaka, Hideki Yamaguchi, Yoko Kubuki, Akira Kitanaka, Hitoshi Matsuoka and Kazuya Shimodaadd Show full author list remove Hide full author list
Viruses 2022, 14(4), 710; https://doi.org/10.3390/v14040710 - 29 Mar 2022
Cited by 3 | Viewed by 1919
Abstract
A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, [...] Read more.
A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL. Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
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17 pages, 1439 KiB  
Article
Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P)
by Junji Yamauchi, Kenichiro Tanabe, Tomoo Sato, Masanori Nakagawa, Eiji Matsuura, Yoshio Tsuboi, Keiko Tamaki, Hirokuni Sakima, Satoshi Ishihara, Yuki Ohta, Naoki Matsumoto, Kenichi Kono, Naoko Yagishita, Natsumi Araya, Katsunori Takahashi, Yasuo Kunitomo, Misako Nagasaka, Ariella Coler-Reilly, Yasuhiro Hasegawa, Abelardo Araujo, Steven Jacobson, Maria Fernanda Rios Grassi, Bernardo Galvão-Castro, Martin Bland, Graham P. Taylor, Fabiola Martin and Yoshihisa Yamanoadd Show full author list remove Hide full author list
Viruses 2022, 14(1), 136; https://doi.org/10.3390/v14010136 - 12 Jan 2022
Cited by 15 | Viewed by 3563
Abstract
Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were [...] Read more.
Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085) Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
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Review

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11 pages, 1529 KiB  
Review
Updates on HTLV-1 Uveitis
by Koju Kamoi, Toshiki Watanabe, Kaoru Uchimaru, Akihiko Okayama, Seiko Kato, Toyotaka Kawamata, Hisako Kurozumi-Karube, Noe Horiguchi, Yuan Zong, Yoshihisa Yamano, Isao Hamaguchi, Yasuhito Nannya, Arinobu Tojo and Kyoko Ohno-Matsui
Viruses 2022, 14(4), 794; https://doi.org/10.3390/v14040794 - 12 Apr 2022
Cited by 14 | Viewed by 3375
Abstract
HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated [...] Read more.
HTLV-1 uveitis (HU) is the third clinical entity to be designated as an HTLV-1-associated disease. Although HU is considered to be the second-most frequent HTLV-1-associated disease in Japan, information on HU is limited compared to that on adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Recent studies have addressed several long-standing uncertainties about HU. HTLV-1-related diseases are known to be caused mainly through vertical transmission (mother-to-child transmission), but emerging HTLV-1 infection by horizontal transmission (such as sexual transmission) has become a major problem in metropolitan areas, such as Tokyo, Japan. Investigation in Tokyo showed that horizontal transmission of HTLV-1 was responsible for HU with severe and persistent ocular inflammation. The development of ATL and HAM is known to be related to a high provirus load and hence involves a long latency period. On the other hand, factors contributing to the development of HU are poorly understood. Recent investigations revealed that severe HU occurs against a background of Graves’ disease despite a low provirus load and short latency period. This review highlights the recent knowledge on HU and provides an update on the topic of HU in consideration of a recent nationwide survey. Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
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8 pages, 216 KiB  
Review
Nationwide Hospital-Based Survey of Adult T-Cell Leukemia/Lymphoma in Japan
by Takeharu Kato, Yoshitaka Imaizumi and Yasushi Miyazaki
Viruses 2022, 14(4), 791; https://doi.org/10.3390/v14040791 - 11 Apr 2022
Viewed by 1817
Abstract
Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of [...] Read more.
Nationwide surveys of adult T-cell leukemia/lymphoma (ATL) have played an important role in helping us to understand the pathophysiology of this disease and analyze its prognosis in Japan. Classifications of clinical subtypes have been proposed based on the results of nationwide surveys of patients with ATL diagnosed in the 1980s. This article highlighted the classification and prognosis of ATL based on different surveys and focused on the comparison of data derived from the available surveys. The 11th nationwide hospital-based survey was conducted in patients with ATL diagnosed in 2010–2011 using the same method as that used in the 1980s survey. The median age of disease onset was 68 years, which was increased compared with previous surveys. While median survival of patients with the acute and lymphoma types had not improved much since the 1980s, the 4-year survival rate was higher. Little improvement in the prognosis was observed for the chronic and smoldering types. The 12th nationwide survey of patients with ATL diagnosed in 2012–2013 also showed an increase in age at onset. Further epidemiological research that includes more cases is needed to deepen our understanding of the actual state of treatment and prognosis of this disease. Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
11 pages, 749 KiB  
Review
Clonal Selection and Evolution of HTLV-1-Infected Cells Driven by Genetic and Epigenetic Alteration
by Makoto Yamagishi, Yutaka Suzuki, Toshiki Watanabe and Kaoru Uchimaru
Viruses 2022, 14(3), 587; https://doi.org/10.3390/v14030587 - 12 Mar 2022
Cited by 9 | Viewed by 3040
Abstract
T cells infected with human T-cell leukemia virus type 1 (HTLV-1) acquire various abnormalities during a long latent period and transform into highly malignant adult T-cell leukemia-lymphoma (ATL) cells. This can be described as “clonal evolution”, in which a single clone evolves into [...] Read more.
T cells infected with human T-cell leukemia virus type 1 (HTLV-1) acquire various abnormalities during a long latent period and transform into highly malignant adult T-cell leukemia-lymphoma (ATL) cells. This can be described as “clonal evolution”, in which a single clone evolves into ATL cells after overcoming various selective pressures in the body of the infected individuals. Many studies have shown that the genome and epigenome contain a variety of abnormalities, which are reflected in gene expression patterns and define the characteristics of the disease. The latest research findings suggest that epigenomic disorders are thought to begin forming early in infection and evolve into ATL through further changes and accentuation as they progress. Genomic abnormalities profoundly affect clonal dominance and tumor cell characteristics in later events. ATL harbors both genomic and epigenomic abnormalities, and an accurate understanding of these can be expected to provide therapeutic opportunities. Full article
(This article belongs to the Special Issue HTLV-1 and HTLV-1-Associated Diseases)
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