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Viruses
Special Issues
Human T-Cell Leukemia Virus (HTLV) Infection and Treatment
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Human T-Cell Leukemia Virus (HTLV) Infection and Treatment

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

Deadline for manuscript submissions: 31 May 2025 | Viewed by 2299

Special Issue Editors

Dr. Cynthia A. Pise-Masison

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Guest Editor
Animal Models and Retroviral Vaccines Section, Center for Cancer Research, National Cancer Institute, Bethesda, MA, USA
Interests: retrovirology; HTLV; animal models; immunology; molecular virology
Dr. Damian F.J. Purcell

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Guest Editor
1. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
2. Global Virus Network Center of Excellence at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
Interests: immunology; viral infectious diseases; bacterial and parasitic infections; emerging infections; hepatitis; HIV

Special Issue Information

Dear Colleagues,

We invite you to contribute original research and/or review to this Special Issue of Viruses that will highlight advances in HTLV-1 research.

The first human retrovirus human T-cell leukemia virus type 1 (HTLV-1) was identified in 1980. As a retrovirus, HTLV-1 integrates into the host genome and causes a persistent lifelong infection. Although the majority of infected individuals remain asymptomatic, a fraction of patients will progress to develop one of several severe diseases. HTLV-1 causes an aggressive fatal malignancy known as adult T-cell leukemia/lymphoma (ATLL), the neurodegenerative disease HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-1 associated uveitis, infectious dermatitis and inflammatory conditions such as respiratory disease, Sjögren’s syndrome, rheumatoid arthritis, fibromyalgia and ulcerative colitis. In addition, HTLV-1 infection is associated with a higher mortality and morbidity. Thus far, no specific differences in viral strains have been identified to account for the differences in disease manifestation. Although a high viral DNA burden in peripheral blood mononuclear cells is a documented risk factor for ATLL and HAM/TSP, and HAM/TSP patients have a higher proviral load in cerebrospinal fluid than in peripheral blood, the virus level alone is not sufficient to differentiate symptomatic patients from healthy carriers, suggesting the importance of other factors, including the host immune response.

While many high-income countries have initiated HTLV-1 screening for blood donations, few other public health measures have been employed to prevent infection or manage/treat ATLL and HAM/TSP. Further, it is difficult to evaluate the public health burden because of the major gaps in the epidemiology of HTLV-1 infection. Even in areas of high prevalence, the awareness of HTLV-1 modes of transmission, disease course and strategies for clinical management are not readily available. Despite the profound impact HTLV-1 has on patient lives, minimal significant progress has been made in developing HTLV-1 vaccines or therapies for these diseases, with the prognosis for ATLL still being poor and HAM/TSP remaining an intractable disease.

Despite being investigated for over 40 years, many fundamental questions in HTLV-1 pathogenesis remain unresolved. In this Special Issue, we will focus on the most recent advances in understanding the mechanism of HTLV infection, with an emphasis on treatment and diagnosis. We will also focus on new developments in biomarkers, prevention, animal models and disease pathogenesis.

Dr. Cynthia A. Pise-Masison
Dr. Damian F.J. Purcell
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. Viruses 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 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
  • HTLV-associated myelopathy/tropical spastic paraparesis
  • adult T-cell leukemia/lymphoma
  • inflammation
  • neurodegeneration
  • therapeutics
  • infectious dermatitis
  • cancer
  • antiviral drugs

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (2 papers)

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18 pages, 5236 KiB  
Article
Dendritic Cells Pulsed with HAM/TSP Exosomes Sensitize CD4 T Cells to Enhance HTLV-1 Infection, Induce Helper T-Cell Polarization, and Decrease Cytotoxic T-Cell Response
by Julie Joseph, Thomas A. Premeaux, Ritesh Tandon, Edward L. Murphy, Roberta Bruhn, Christophe Nicot, Bobby Brooke Herrera, Alexander Lemenze, Reem Alatrash, Prince Baffour Tonto, Lishomwa C. Ndhlovu and Pooja Jain
Viruses 2024, 16(9), 1443; https://doi.org/10.3390/v16091443 - 10 Sep 2024
Viewed by 1210
Abstract
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive demyelinating disease of the spinal cord due to chronic inflammation. Hallmarks of disease pathology include dysfunctional anti-viral responses and the infiltration of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ T cells in the central nervous [...] Read more.
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive demyelinating disease of the spinal cord due to chronic inflammation. Hallmarks of disease pathology include dysfunctional anti-viral responses and the infiltration of HTLV-1-infected CD4+ T cells and HTLV-1-specific CD8+ T cells in the central nervous system. HAM/TSP individuals exhibit CD4+ and CD8+ T cells with elevated co-expression of multiple inhibitory immune checkpoint proteins (ICPs), but ICP blockade strategies can only partially restore CD8+ T-cell effector function. Exosomes, small extracellular vesicles, can enhance the spread of viral infections and blunt anti-viral responses. Here, we evaluated the impact of exosomes isolated from HTLV-1-infected cells and HAM/TSP patient sera on dendritic cell (DC) and T-cell phenotypes and function. We observed that exosomes derived from HTLV-infected cell lines (OSP2) elicit proinflammatory cytokine responses in DCs, promote helper CD4+ T-cell polarization, and suppress CD8+ T-cell effector function. Furthermore, exosomes from individuals with HAM/TSP stimulate CD4+ T-cell polarization, marked by increased Th1 and regulatory T-cell differentiation. We conclude that exosomes in the setting of HAM/TSP are detrimental to DC and T-cell function and may contribute to the progression of pathology with HTLV-1 infection. Full article
(This article belongs to the Special Issue Human T-Cell Leukemia Virus (HTLV) Infection and Treatment)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Exosomes activate and elicit proinflammatory responses in dendritic cells. (<b>A</b>) Representative phenotype of myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) population differences with exosome stimulation (<span class="html-italic">n</span> = 4). GMFI levels of CD40, CD80, and CD86 in mDC and pDC populations untreated or stimulated with exosomes. Bars represent mean ± standard deviation (SD). (<b>B</b>) Expression of cytokines associated with Th1, Th2, Th17, and Treg polarization in total DCs stimulated with OSP2 cell-derived exosomes or LPS. Cytokines were grouped according to associated Th1 (IFN-γ, TNF-α, and IL-2), Th2 (IL-4, IL-12a, and IL-13), Th17 (IL-6 and IL-17a), and Treg (IL-10 and TGF-β) subsets. (<b>C</b>) Cytokine levels (pg/mL) in supernatants of mDCs (<b>left</b>) and pDCs (<b>right</b>) untreated or exosome-stimulated. Statistical differences were determined by one-way ANOVA, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005.</p> Full article ">Figure 2
<p>Dendritic cell-pulsed exosomes polarize T cells. (<b>A</b>) Exosome stimulation schematic and representative gating strategy. Donor CD3+ T cells and matched total DCs were isolated (<span class="html-italic">n</span> = 4). (<b>B</b>) DCs were exposed to OSP2-derived exosomes for 24 h and subsequently co-incubated with donor-matched T cells for another 24 h. Absolute count of CD4+ T-cells expressing subtype-associated markers: Th1 (IFN-γ, CCR5), Th2 (IL-4, CCR4), Th17 (IL-17, CCR6), and Treg (CD25, FoxP3). Quantification (pg/mL) of IFN-γ, TGF-β, and TNF-α cytokine levels in exosome-stimulated DC–T-cell co-culture (<span class="html-italic">n</span> = 3). (<b>C</b>) Representative flow plots and quantification (<span class="html-italic">n</span> = 4) of percent positive CD4+ T cells expressing functional markers of IFN-γ, IL-4, IL-17a, CD25, CCR5, and CCR6 after stimulation with OSP2 cell-derived exosomes. Bars represent mean ± standard deviation (SD). Statistical differences were determined by one-way ANOVA, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 2 Cont.
<p>Dendritic cell-pulsed exosomes polarize T cells. (<b>A</b>) Exosome stimulation schematic and representative gating strategy. Donor CD3+ T cells and matched total DCs were isolated (<span class="html-italic">n</span> = 4). (<b>B</b>) DCs were exposed to OSP2-derived exosomes for 24 h and subsequently co-incubated with donor-matched T cells for another 24 h. Absolute count of CD4+ T-cells expressing subtype-associated markers: Th1 (IFN-γ, CCR5), Th2 (IL-4, CCR4), Th17 (IL-17, CCR6), and Treg (CD25, FoxP3). Quantification (pg/mL) of IFN-γ, TGF-β, and TNF-α cytokine levels in exosome-stimulated DC–T-cell co-culture (<span class="html-italic">n</span> = 3). (<b>C</b>) Representative flow plots and quantification (<span class="html-italic">n</span> = 4) of percent positive CD4+ T cells expressing functional markers of IFN-γ, IL-4, IL-17a, CD25, CCR5, and CCR6 after stimulation with OSP2 cell-derived exosomes. Bars represent mean ± standard deviation (SD). Statistical differences were determined by one-way ANOVA, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 3
<p>Immune checkpoint and anti-viral cytokine expression of exosomes from individuals with HAM/TSP. (<b>A</b>) Representative NTA of exosomes isolated from asymptomatic carrier (AC, <span class="html-italic">n</span> = 1) and HAM/TSP (HAM, <span class="html-italic">n</span> = 3) patient sera in individuals infected with HTLV-1 or HTLV-2. (<b>B</b>) Quantification of immune checkpoint proteins BTLA, LAG-3, PD-1, and PD-L2 in exosomes from AC and HAM/TSP patient sera from individuals infected with HTLV-1, left, or HTLV-2, right. (<b>C</b>) Quantification of IFN-γ and TNF-α levels in exosomes from AC and HAM/TSP patient sera from individuals infected with HTLV-1, left, or HTLV-2, right. Bars represent mean ± standard deviation (SD). Statistical differences were determined by unpaired two-tailed T-tests of technical replicates, * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 4
<p>HAM/TSP exosomes skew Th1/Treg responses and sensitize cells toward infection. (<b>A</b>) Exosome stimulation schematic and representative gating strategy. CD3+ T cells and total DCs were isolated from matched donors (<span class="html-italic">n</span> = 4). DCs were stimulated with exosomes from HTLV-1 patient sera for 24 h and subsequently co-incubated with donor-matched T cells for another 24 h. Differences in GMFI of representative markers are plotted. Bottom, absolute count of CD4+ T cells expressing subtype-associated markers: Th1 (IFN-y and CCR5), Th2 (IL-4 and CCR4), Th17 (IL-17 and CCR6), and Treg (CD25 and FoxP3). (<b>B</b>) Quantification (pg/mL) of IFN-γ, TGF-β, and TNF-α cytokine levels in patient exosome-stimulated DC–T-cell co-culture. (<b>C</b>) Representative flow plots and quantification (<span class="html-italic">n</span> = 4) of percent positive CD4+ T cells expressing functional markers of IFN-γ, IL-4, IL-17a, CD25, CCR5, and CCR6 after stimulation with HTLV-1 patient-derived exosomes. Bars represent mean ± standard deviation (SD). Statistical differences were determined by one-way ANOVA, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 4 Cont.
<p>HAM/TSP exosomes skew Th1/Treg responses and sensitize cells toward infection. (<b>A</b>) Exosome stimulation schematic and representative gating strategy. CD3+ T cells and total DCs were isolated from matched donors (<span class="html-italic">n</span> = 4). DCs were stimulated with exosomes from HTLV-1 patient sera for 24 h and subsequently co-incubated with donor-matched T cells for another 24 h. Differences in GMFI of representative markers are plotted. Bottom, absolute count of CD4+ T cells expressing subtype-associated markers: Th1 (IFN-y and CCR5), Th2 (IL-4 and CCR4), Th17 (IL-17 and CCR6), and Treg (CD25 and FoxP3). (<b>B</b>) Quantification (pg/mL) of IFN-γ, TGF-β, and TNF-α cytokine levels in patient exosome-stimulated DC–T-cell co-culture. (<b>C</b>) Representative flow plots and quantification (<span class="html-italic">n</span> = 4) of percent positive CD4+ T cells expressing functional markers of IFN-γ, IL-4, IL-17a, CD25, CCR5, and CCR6 after stimulation with HTLV-1 patient-derived exosomes. Bars represent mean ± standard deviation (SD). Statistical differences were determined by one-way ANOVA, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.005, *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 5
<p>HAM/TSP exosomes skew T cells to Th1/Treg profiles in patient PBMCs. (<b>A</b>) Representative flow plots and quantification (<span class="html-italic">n</span> = 4) of the polarization of T cells from individuals with HTLV-1 with or without HTLV-1 sera-derived exosomes. (<b>B</b>) Representative flow plots and quantification (<span class="html-italic">n</span> = 4) of HTLV-1-infected patient CD4+ T cells with or without HTLV-1 sera-derived exosome stimulation. Bars represent mean ± standard deviation (SD). Statistical differences were determined by one-way ANOVA, * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 6
<p>Exosomes diminish CD8+ T-cell activity. (<b>A</b>) Schematic of treatment and gating strategy of CD8+ T cells. CD3+ T cells and total DCs were isolated from matched donors (<span class="html-italic">n</span> = 4). DCs were stimulated with OSP2-derived exosomes for 24 h and subsequently co-incubated with donor-matched T cells for another 24 h. Absolute counts of CD8+ T cells expressing MIP-1a, Granzyme B, Perforin, IFN-γ, PD-1, and Ki67 after co-incubation with exosome-pulsed DCs. (<b>B</b>) Absolute counts of CD8+ T cells after CD3+/CD28+ activation and stimulation with OSP2 exosomes alone, or exosomes incubated with a cocktail of anti-PD-L2, anti-BTLA, anti-LAG-3, and anti-PD-1 blocking antibodies. (<b>C</b>) Absolute counts of CD8+ T cells expressing MIP-1a, Granzyme B, Perforin, IFN-γ, PD-1, and Ki67 in HTLV-1-infected patient T cells (<span class="html-italic">n</span> = 4) stimulated with patient sera exosomes alone or exosomes incubated with a cocktail of anti-PD-L2, anti-BTLA, anti-LAG-3, and anti-PD-1 blocking antibodies. Counts were determined by experiments with <span class="html-italic">n</span> = 3/4 healthy donors, and error bars represent SEM of donor variation. Bars represent mean ± standard deviation (SD). Statistical differences were determined by one-way ANOVA. (<b>D</b>) Western blot and densitometry of CD3/CD28-stimulated T cells treated with Jurkat and OSP2 exosomes alone, or exosomes incubated with a cocktail of anti-PD-L2, anti-BTLA, anti-LAG-3, and anti-PD-1 blocking antibodies. Blot was probed for phosphorylated AKT or ERK. Error bars represent SEM of blot variation; statistical differences were determined by paired two-tailed T-test, * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">

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9 pages, 1483 KiB  
Brief Report
Evaluation of QuantiFERON-TB Gold for the Diagnosis of Mycobacterium tuberculosis Infection in HTLV-1-Infected Patients
by Luana Leandro Gois, Natália Barbosa Carvalho, Fred Luciano Neves Santos, Carlos Gustavo Regis-Silva, Thainá Gonçalves Tolentino Figueiredo, Bernardo Galvão-Castro, Edgar Marcelino Carvalho and Maria Fernanda Rios Grassi
Viruses 2024, 16(12), 1873; https://doi.org/10.3390/v16121873 - 30 Nov 2024
Viewed by 669
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is associated with an increased risk of tuberculosis (TB). This study aimed to evaluate the performance of the QuantiFERON-TB Gold (QFT) test for the diagnosis of Mycobacterium tuberculosis (MTB) infection in HTLV-1-infected individuals. HTLV-1-infected participants were [...] Read more.
Human T-cell leukemia virus type 1 (HTLV-1) is associated with an increased risk of tuberculosis (TB). This study aimed to evaluate the performance of the QuantiFERON-TB Gold (QFT) test for the diagnosis of Mycobacterium tuberculosis (MTB) infection in HTLV-1-infected individuals. HTLV-1-infected participants were divided into four groups: HTLV-1-infected individuals with a history of tuberculosis (HTLV/TB), individuals with positive HTLV and tuberculin skin tests (HTLV/TST+) or negative TST (HTLV/TST−), and HTLV-1-negative individuals with positive TST results (HN/TST+). We compared the diagnostic performance of the QFT assay with that of the TST as a reference and evaluated test sensitivity, specificity, accuracy, likelihood ratio, and diagnostic odds ratio. The results showed a higher frequency of positive TST results and induration diameter ≥10 mm in HTLV-1-infected individuals than in the controls. The QFT test was more frequently positive in the HTLV/TB group than in the other groups, while a combined analysis of HTLV/TB and HTLV/TST+ indicated a QFT sensitivity of 57.5%. No significant differences were found in the other diagnostic performance measures, as QFT test results were in agreement with TST results, particularly in TST-negative individuals. Given the low sensitivity of QFT for LTBI in individuals infected with HTLV-1, the TST may be preferable in regions where both infections are endemic. Full article
(This article belongs to the Special Issue Human T-Cell Leukemia Virus (HTLV) Infection and Treatment)
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Figure 1

Figure 1
<p>Flowchart illustrating study design in conformity with the Standards for Reporting of Diagnostic Accuracy Studies (STARD).</p> Full article ">Figure 2
<p>Diagnostic parameters used to evaluate the performance of the QuantiFERON-TB (QFT) assay in detecting TST positivity and previous tuberculosis infection (TB) among individuals with HTLV-1. HN (HTLV-1-negative); HTLV (HTLV-1-infected individuals); TB (tuberculosis); TST (tuberculin skin test).</p> Full article ">
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