Establishing Phenotypic Features Associated with Morbidity in Human T-Cell Lymphotropic Virus Type 1 Infection

ABSTRACT The human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HT). Although it is widely believed that virus infection and host immune response are involved in the pathogenic mechanisms, the role of the immune system in the development and/or maintenance of HT remains unknown. We performed an analysis of the peripheral blood leukocyte phenotype for two different subcohorts of HTLV-1-infected individuals to verify the existence of similar immunological alterations, possible laboratory markers for HT. The leukocyte population balance, the activation status of the T lymphocytes, and the cellular migratory potential of T lymphocytes, monocytes, and neutrophils were evaluated in the peripheral blood of HTLV-1-infected individuals classified as asymptomatic individuals, oligosymptomatic individuals, and individuals with HT. Data analysis demonstrated that a decreased percentage of B cells, resulting in an increased T cell/B cell ratio and an increase in the CD8+ HLA-DR+ T lymphocytes, exclusively in the HT group could be identified in both subcohorts, suggesting its possible use as a potential immunological marker for HT for use in the laboratory. Moreover, analysis of likelihood ratios showed that if an HTLV-1-infected individual demonstrated B-cell percentages lower than 7.0%, a T cell/B cell ratio higher than 11, or a percentage of CD8+ HLA-DR+ T lymphocytes higher than 70.0%, this individual would have, respectively, a 12-, 13-, or 22-times-greater chance of belonging to the HT group. Based on these data, we propose that the T cell/B cell ratios and percentages of circulating B cells and activated CD8+ T lymphocytes in HTLV-1-infected patients are important immunological indicators which could help clinicians monitor HTLV-1 infection and differentiate the HT group from the asymptomatic and oligosymptomatic groups.

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The Role of Cytotoxic T Lymphocytes in Human T-cell Lymphotropic Virus Type 1 Infection

Journal of Theoretical Biology ◽

10.1006/jtbi.2000.2156 ◽

2000 ◽

Vol 207 (1) ◽

pp. 65-79 ◽

Cited By ~ 17

Author(s):

BECCA ASQUITH ◽

CHARLES R.M. BANGHAM

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Virus Type ◽

Human T Cell

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AB0268 HUMAN T-CELL LEUKAEMIA VIRUS TYPE 1 MAY INVALIDATE T-SPOT.TB RESULTS AMONG RHEUMATOID ARTHRITIS PATIENTS: A RETROSPECTIVE OBSERVATIONAL STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1588 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1432.1-1433

Author(s):

K. Umekita ◽

Y. Hashiba ◽

R. Kudou ◽

S. Miyauchi ◽

M. Kimura ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Type ◽

Peripheral Blood ◽

Medical Records ◽

Cell Leukaemia ◽

Leukaemia Virus ◽

Human T Cell ◽

Ifn Γ

Background:In clinical rheumatology, interferon-γ release assays (IGRAs) have been reported as a useful diagnostic test for latent tuberculosis infection (LTBI) before beginning the administration of biologics such as anti-TNF therapies (1). CD4-positive T cells are the main target in Human T-cell leukaemia virus type 1 (HTLV-1) infection. Several reports suggest that the reaction of tuberculin skin test (TST) is attenuated in HTLV-1-positive individuals compared with that in HTLV-1-negative individuals (2). However, it remains unclear whether IGRAs are reliable for detecting TB infection among HTLV-1-positive RA patients.Objectives:The present study aimed to investigate the usefulness of the T-SPOT.TBassay in HTLV-1-positive RA patients. In addition, the association between the existence of IFN-γ producing T cells and HTLV-1 proviral loads (PVLs) in HTLV-1-positive RA patients was analysed on the basis of the T-SPOT.TBassay results.Methods:We reviewed the medical records of 75 HTLV-1-negative and 29 HTLV-1-positive RA patients were suspected cases of LTBI and evaluated using the T-SPOT.TBassay as a clinical practice from April 2012 to July 2019. The results of T-SPOT.TBwere collected from medical records, retrospectively. Peripheral blood samples were obtained from HTLV-1-positive RA patients for the analysis of HTLV-1 PVLs values. The study protocol was approved by the research ethics committees of our hospitals.Results:Approximately 55% of the HTLV-1-positive RA patients showed invalid results for the T-SPOT.TBassay (p < 0.0001); the cause of invalid results was a spot-forming count of >10 spots in the negative controls of the T-SPOT.TBassay among HTLV-1-positive RA patients. Among HTLV-1-positive RA patients, HTLV-1 PVL values were significantly higher in 16 patients who showed invalid results than in 13 patients who did not (p = 0.003). There were no between-group differences in female patient ratio, age, RA disease activity and therapeutic regimens. IFN-γ producing cells were detected in the peripheral blood of HTLV-1-positive RA patients without stimulation with TB-specific antigens.Conclusion:The incidence of invalid results for the T-SPOT.TBassay has been reported to be as low as 0.6% (3). The results of this assay for screening of LTBI in HTLV-1-positive RA patients should be interpreted with caution. Furthermore, our results show that an increase in IFN-γ producing T cell numbers due to HTLV-1 infection in RA patients may affect the pathogenesis of RA.References:[1]Iannone, F., et al.J. Rheumatol. Suppl.91, 41-46 (2014).[2]Tachibana, N., et al.Int. J. Cancer42, 829-831 (1988).[3]Rego, K., et al.Tuberculosis (Edinb.)108, 178-185 (2018).Acknowledgments:We would like to thank Dr Yuki Hashikura and Ms Yuki Kaseda of the University of Miyazaki for their technical support in this work. We would also like to acknowledge Ms Yumiko Kai at the Institute of Rheumatology, Zenjinkai Shimin-no-Mori Hospital, for her help in data management.A part this work was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. JP19ek0109356), a Health and Labor Sciences Research Grant on Rare and Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan (Grant No. 19FC1007), and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.Disclosure of Interests:Kunihiko Umekita Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Bristol-Myers Squibb, Yayoi Hashiba: None declared, Risa Kudou: None declared, Shunichi Miyauchi: None declared, Masatoshi Kimura: None declared, Motohiro Matsuda: None declared, Chihiro Iwao: None declared, Yumi Kariya: None declared, Takeshi Kawaguchi: None declared, Katoko Takajo: None declared, Koushou Iwao: None declared, Yuuki Rikitake: None declared, Ichiro Takajo: None declared, Toshihiko Hidaka Paid instructor for: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Speakers bureau: Astellas Pharma Inc. Chugai Pharma Inc. Tanabe-Mitsubishi Pharma Inc., Akihiko Okayama: None declared

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Effect of Lamivudine on Transmission of Human T-Cell Lymphotropic Virus Type 1 to Adult Peripheral Blood Mononuclear Cells In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.9.3080-3083.2002 ◽

2002 ◽

Vol 46 (9) ◽

pp. 3080-3083 ◽

Cited By ~ 16

Author(s):

Emanuela Balestrieri ◽

Giancarlo Forte ◽

Claudia Matteucci ◽

Antonio Mastino ◽

Beatrice Macchi

Keyword(s):

T Cell ◽

Virus Type ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Human T Cell ◽

Blood Mononuclear Cells

ABSTRACT The effects of lamivudine (3TC) on in vitro infection of peripheral blood mononuclear cells (PBMC) from healthy donors with human T-cell lymphotropic virus type 1 (HTLV-1) were investigated. Direct measures of viral replication (viral DNA, RNA, and protein) all gave similar, very high 50% inhibitory concentrations in comparison with those previously reported for zidovudine. Nevertheless, 3TC inhibited HTLV-1-driven long-term growth of infected PBMC in vitro at concentrations (6.25 μM) which had poor or no direct antiviral effects, suggesting that another mechanism may be playing a role.

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Immortalization of CD4+ and CD8+ T Lymphocytes by Human T-Cell Leukemia Virus Type 1 Tax Mutants Expressed in a Functional Molecular Clone

Journal of Virology ◽

10.1128/jvi.73.6.4856-4865.1999 ◽

1999 ◽

Vol 73 (6) ◽

pp. 4856-4865 ◽

Cited By ~ 139

Author(s):

Michael D. Robek ◽

Lee Ratner

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Virus Type ◽

Leukemia Virus ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Molecular Clone ◽

Human T Cell ◽

T Cell Leukemia Virus

ABSTRACT The human T-cell leukemia virus type 1 (HTLV-1) transcriptionaltrans-activator Tax has been demonstrated to have transforming activity in multiple cell culture and transgenic-mouse models. In addition to activating transcription from the viral long terminal repeat (LTR) through the cyclic AMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors, Tax activates the expression of multiple cellular promoters through the NF-κB pathway of transcriptional activation. The Tax mutants M22 and M47 have previously been demonstrated to selectively abrogate the ability of Tax to activate transcription through the NF-κB or CREB/ATF pathway, respectively. These mutations were introduced in the tax gene of the ACH functional molecular clone of HTLV-1, and virus produced from the mutant ACH clones was examined for the ability to replicate and immortalize primary human lymphocytes. While virus derived from the clone containing the M47 mutation retained the ability to immortalize T lymphocytes, the M22 mutant lost the ability to immortalize infected cells. These results indicate that activation of the CREB/ATF pathway by Tax is dispensable for the immortalization of T cells by HTLV-1, whereas activation of the NF-κB pathway may be critical.

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A Chimeric Human T-Cell Lymphotropic Virus Type 1 with the Envelope Glycoprotein of Moloney Murine Leukemia Virus Is Infectious for Murine Cells

Journal of Virology ◽

10.1128/jvi.76.15.7883-7889.2002 ◽

2002 ◽

Vol 76 (15) ◽

pp. 7883-7889 ◽

Cited By ~ 18

Author(s):

Frédéric Delebecque ◽

Karin Pramberger ◽

Marie-Christine Prévost ◽

Michel Brahic ◽

Frédéric Tangy

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Virus Type ◽

Envelope Glycoprotein ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Moloney Murine Leukemia Virus ◽

Human T Cell ◽

Murine Leukemia

ABSTRACT We constructed a chimeric human T-cell lymphotropic virus type 1 (HTLV-1) provirus in which the original envelope precursor sequence was replaced by that of ecotropic Moloney murine leukemia virus (Mo-MuLV). Chimeric particles produced by transient transfection of this chimeric provirus were infectious for murine cells, such as NIH 3T3 fibroblasts, lymphoid EL4 cells, and primary CD4+ T lymphocytes, whereas HTLV-1 particles were not. The infectivity of chimeric particles increased 10 times when the R peptide located at the carboxy terminus of the MuLV envelope glycoprotein was deleted. Primary murine CD4+ T lymphocytes, infected by the ΔR chimeric virus, released particles that could spread the infection to other naive murine lymphoid cells. This chimeric virus, with the Mo-MuLV envelope glycoprotein and the replication characteristics of HTLV-1, should be useful in studying the pathogenesis of HTLV-1 in a mouse model.

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Expansion of Natural Killer Cells in Peripheral Blood in a Japanese Elderly with Human T-Cell Lymphotropic Virus Type 1-Related Skin Lesions

Case Reports in Dermatological Medicine ◽

10.1155/2014/937513 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4

Author(s):

Shinsaku Imashuku ◽

Naoko Kudo ◽

Kagekatsu Kubo ◽

Kouichi Ohshima

Keyword(s):

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Virus Type ◽

Peripheral Blood ◽

Skin Lesions ◽

Cd4 Cells ◽

Human T Cell ◽

Japanese Elderly

Natural killer (NK) cells were proposed to play an important role in the pathogenesis of human T-cell lymphotropic virus type 1- (HTLV-1-) associated neurologic disease. Our patient was a 77-year-old Japanese man, who had been treated for infective dermatitis associated with HTLV-1 for nearly 10 years. When referred to us, he had facial eczema/edema as well as extensive dermatitis at the neck/upper chest and nuchal area/upper back regions. Dermal lesions had CD3+CD4+ cells, but no NK cells. Flow cytometry of his peripheral blood showed a phenotype of CD2+ (97%), CD3+ (17%), CD4+ (12%), CD7+ (94%), CD8+ (6%), CD11c+ (70%), CD16+ (82%), CD19+ (0%), CD20+ (0%), CD56+ (67%), HLA-DR+ (68%), and NKp46+ (36%). Absolute numbers of CD56+NK cells in the peripheral blood were in a range of 986/μL–1,270/μL. The expanded NK cells in the peripheral blood are considered to be reactive, to maintain the confinement of the HTLV-1-positive CD4+ cells in the skin, and to prevent the progression of the disease.

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Interaction of the human T-cell lymphotropic virus type 1 tax transactivator with transcription factor IIA.

Molecular and Cellular Biology ◽

10.1128/mcb.16.9.4656 ◽

1996 ◽

Vol 16 (9) ◽

pp. 4656-4664 ◽

Cited By ~ 35

Author(s):

K E Clemens ◽

G Piras ◽

M F Radonovich ◽

K S Choi ◽

J F Duvall ◽

...

Keyword(s):

Transcription Factor ◽

T Cell ◽

T Lymphocytes ◽

Virus Type ◽

Expression Vectors ◽

Human T Lymphocytes ◽

Cell Extracts ◽

Human T Cell

The Tax protein of human T-cell lymphotropic virus type 1 (HTLV-1) is a 40-kDa transcriptional activator which is critical for HTLV-1 gene regulation and virus-induced cellular transformation. Tax is localized to the DNA through its interaction with the site-specific activators cyclic AMP-responsive element-binding protein, NF-kappaB, and serum response factor. It has been suggested that the recruitment of Tax to the DNA positions Tax for interaction with the basal transcriptional machinery. On the basis of several independent assays, we now report a physical and functional interaction between Tax and the transcription factor, TFIIA. First, Tax was found to interact with the 35-kDa (alpha) subunit of TFIIA in the yeast two-hybrid interaction system. Importantly, two previously characterized mutants with point mutations in Tax, M32 (Y196A, K197S) and M41 (H287A, P288S), which were shown to be defective in Tax-activated transcription were unable to interact with TFIIA in this assay. Second, a glutathione-S-transferase (GST) affinity-binding assay showed that the interaction of holo-TFIIA with GST-Tax was 20-fold higher than that observed with either the GST-Tax M32 activation mutant or the GST control. Third, a coimmunoprecipitation assay showed that in HTLV-1-infected human T lymphocytes, Tax and TFIIA were associated. Finally, TFIIA facilitates Tax transactivation in vitro and in vivo. In vitro transcription studies showed reduced levels of Tax-activated transcription in cell extracts depleted of TFIIA. In addition, transfection of human T lymphocytes with TFIIA expression vectors enhanced Tax-activated transcription of an HTLV-1 long terminal repeat-chloramphenicol acetyltransferase reporter construct. Our study suggests that the interaction of Tax with the transcription factor TFIIA may play a role in Tax-mediated transcriptional activation.

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Rational design of chimeric Multiepitope Based Vaccine (MEBV) against human T-cell lymphotropic virus type 1: An integrated vaccine informatics and molecular docking based approach

PLoS ONE ◽

10.1371/journal.pone.0258443 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0258443

Author(s):

Muhammad Hamza Tariq ◽

Rashid Bhatti ◽

Nida Fatima Ali ◽

Usman Ali Ashfaq ◽

Farah Shahid ◽

...

Keyword(s):

Molecular Docking ◽

T Cell ◽

T Lymphocytes ◽

Virus Type ◽

Rational Design ◽

Cell Mediated Immunity ◽

T Cell Epitopes ◽

Human T Cell ◽

Antigenic Properties

Human T-cell lymphotropic virus type 1 (HTLV-1) is an infectious virus that has been linked to adult T cell leukemia /lymphoma, aggressive CD4-T cell malignancy and many other immune-related medical illnesses. So far, no effective vaccine is known to combat HTLV-1, hence, the current research work was performed to design a potential multi-epitope-based subunit vaccine (MEBV) by adopting the latest methodology of reverse vaccinology. Briefly, three highly antigenic proteins (Glycoprotein, Accessory protein, and Tax protein) with no or minimal (<37%) similarity with human proteome were sorted out and potential B- and T-cell epitopes were forecasted from them. Highly antigenic, immunogenic, non-toxic, non-allergenic and overlapping epitopes were short-listed for vaccine development. The chosen T-cell epitopes displayed a strong binding affinity with their corresponding Human Leukocyte Antigen alleles and demonstrated 95.8% coverage of the world’s population. Finally, nine Cytotoxic T Lymphocytes, six Helper T Lymphocytes and five Linear B Lymphocytes epitopes, joint through linkers and adjuvant, were exploited to design the final MEBV construct, comprising of 382 amino acids. The developed MEBV structure showed highly antigenic properties while being non-toxic, soluble, non-allergenic, and stable in nature. Moreover, disulphide engineering further enhanced the stability of the final vaccine protein. Additionally, Molecular docking analysis and Molecular Dynamics (MD) simulations confirmed the strong association between MEBV construct and human pathogenic immune receptor TLR-3. Repeated-exposure simulations and Immune simulations ensured the rapid antigen clearance and higher levels of cell-mediated immunity, respectively. Furthermore, MEBV codon optimization and in-silico cloning was carried out to confirm its augmented expression. Results of our experiments suggested that the proposed MEBV could be a potential immunogenic against HTLV-1; nevertheless, additional wet lab experiments are needed to elucidate our conclusion.

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