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

Deadline for manuscript submissions: 30 November 2024 | Viewed by 20056

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Special Issue Editors

Dr. Arnold B. Rabson

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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

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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

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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

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Research

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19 pages, 4881 KiB

Open AccessArticle

A Novel Tax-Responsive Reporter T-Cell Line to Analyze Infection of HTLV-1

by Stefanie Heym, Pauline Krebs, Kristin Ott, Norbert Donhauser, Laura M. Kemeter, Florian Simon, Sebastian Millen and Andrea K. Thoma-Kress

Pathogens 2024, 13(11), 1015; https://doi.org/10.3390/pathogens13111015 - 19 Nov 2024

Viewed by 350

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infects CD4⁺ T-cells through close cell–cell contacts. The viral Tax-1 (Tax) protein regulates transcription by transactivating the HTLV-1 U3R promoter in the 5′ long terminal repeat of the integrated provirus. Here, we generated a clonal Tax-responsive T-cell line to track HTLV-1 infection at the single-cell level using flow cytometry, bypassing intracellular viral protein staining. Jurkat T-cells stably transduced with the SMPU vector carrying green fluorescent protein (GFP) under control of 18 × 21 bp Tax-responsive element repeats of the U3R were evaluated. Among 40 clones analyzed for Tax responsiveness, the top two were characterized. Upon overexpression of Tax, over 40% of the cells showed GFP positivity, and approximately 90% of the Tax-positive cells were GFP-positive, indicating efficient reporter activity. However, with CREB-deficient Tax mutant M47, both total GFP-positive cell counts and those within the Tax-positive group significantly decreased. Co-culture with chronically HTLV-1-infected MT-2 or C91-PL cells led to an average of 0.9% or 2.4% GFP-positive cells, respectively, confirming the suitability to monitor HTLV-1 transmission and that HTLV-1 infection is very low. Thus, the novel Tax-responsive reporter T-cell line is a suitable tool to monitor infection of HTLV-1 on the single-cell level. Full article

(This article belongs to the Special Issue New Directions in HTLV-1 Research)

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12 pages, 1553 KiB

Open AccessArticle

Radiological Changes in the Spinal Cord and Brain of Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)

by Emily H. Stack, Serhat V. Okar, Tianxia Wu, Mallory Stack, Yair Mina, María Gaitán, Shila Azodi, Will Frazier, Joan Ohayon, Irene C. M. Cortese, Daniel S. Reich, Govind Nair and Steven Jacobson

Pathogens 2024, 13(11), 920; https://doi.org/10.3390/pathogens13110920 - 22 Oct 2024

Viewed by 434

Abstract

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disorder and shares many radiological and clinical features with other more prevalent myelopathies. Here, we quantified spinal cord and brain volumes in adults with HAM/TSP in comparison with healthy volunteers (HVs) and individuals diagnosed with relapsing–remitting or progressive multiple sclerosis (RRMS or P-MS). Clinical disability and MRI were assessed in 24 HVs, 43 HAM/TSP subjects, and 46 MS subjects. Spinal cord cross-sectional area (SCCSA) and brain tissue volumes were measured and compared. HAM/TSP subjects had significantly lower SCCSA corresponding to cervical levels 2 and 3 (C2–3) (54.0 ± 8 mm²), cervical levels 4 and 5 (C4–5) (57.8 ± 8 mm²), and thoracic levels 4 to 9 (T4–9) (22.7 ± 4 mm²) and significantly elevated brain white matter hyperintensity (WMH) fraction (0.004 ± 0.008) compared to the HVs (C2–3: 69.4 ± 8 mm², C4–5: 75.1 ± 9 mm², T4–9: 34.1 ± 4 mm²; all p < 0.0001; and WMH: 0.0005 ± 0.0007; p < 0.001). In the HAM/TSP subjects, SCCSA at all levels but not WMH showed a significant correlation with clinical disability scores. WMH in HAM/TSP subjects, therefore, may not be related to clinical disability. SCCSA in our limited RRMS cohort was higher than the HAM/TSP cohort (C2–3: 67.6 ± 8 mm², C4–5: 72.7 ± 9 mm², T4–9: 33.4 ± 5 mm²; all p < 0.0001) and WMH was lower than in P-MS subjects (p = 0.0067). Principal component analysis suggested that SCCSA and WMH may be used to differentiate HAM/TSP from MS. Understanding these differences msay help establish early diagnostic criteria for HAM/TSP patients. Full article

(This article belongs to the Special Issue New Directions in HTLV-1 Research)

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23 pages, 3559 KiB

Open AccessEditor’s ChoiceArticle

Complete Rescue of HTLV-1_p12KO 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

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Abstract

The transient depletion of monocytes alone prior to exposure of macaques to HTLV-1 enhances both HTLV-1_WT (wild type) and HTLV-1_p12KO (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-1_WT or HTLV-1_p12KO. Remarkably, triple depletion resulted in exacerbation of infection by both viruses and complete rescue of HTLV-1_p12KO 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-1_WT or HTLV-1_p12KO 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-1_WT. 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

Open AccessArticle

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

Cited by 1 | Viewed by 1516

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 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

Open AccessArticle

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 1839

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 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

Open AccessArticle

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 1962

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, 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

Open AccessArticle

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 - 3 Feb 2023

Cited by 2 | Viewed by 2727

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 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)

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17 pages, 14185 KiB

Open AccessReview

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

Cited by 3 | Viewed by 2243

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 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

Open AccessReview

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 2573

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 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

Open AccessReview

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 3 | Viewed by 2501

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 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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