<i>TAX</i>-mRNA-Carrying Exosomes from Human T Cell Lymphotropic Virus Type 1-Infected Cells Can Induce Interferon-Gamma Production<i>In Vitro</i>

Otaguiri, Katia Kaori; Santos, Daniela Soares; Slavov, Svetoslav Nanev; Depieri, Lívia Vieira; Palma, Patrícia Vianna Bonini; Meirelles, Flávio Vieira; Covas, Dimas Tadeu; Silveira, Juliano Coelho da; Kashima, Simone

doi:10.1089/aid.2018.0115

Cited by 17 publications

(20 citation statements)

References 34 publications

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“…The presence of Tax in EVs are in line with previous findings of EV associated Tax in cell lines, PBMCs, and CSF from HAM/TSP patients (Jaworski et al, 2014a; El-Saghir et al, 2016; Barclay et al, 2017a; Anderson M.R. et al, 2018; Otaguiri et al, 2018). Moreover, they show that an IR treated infected cell may potentially contain significantly higher levels of intracellular Tax.…”

Section: Discussionsupporting

confidence: 91%

HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact

et al. 2019

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Human T-cell leukemia virus-1 (HTLV-1) is a neglected and incurable retrovirus estimated to infect 5 to 10 million worldwide. Specific indigenous Australian populations report infection rates of more than 40%, suggesting a potential evolution of the virus with global implications. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL), and a neurological disease named HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Even though HTLV-1 transmission primarily occurs from cell-to-cell, there is still a gap of knowledge regarding the mechanisms of viral spread and disease progression. We have recently shown that Extracellular Vesicles (EVs) ubiquitously produced by cells may be used by HTLV-1 to transport viral proteins and RNA, and elicit adverse effects on recipient uninfected cells. The viral proteins Tax and HBZ are involved in disease progression and impairment of autophagy in infected cells. Here, we show that activation of HTLV-1 via ionizing radiation (IR) causes a significant increase of intracellular Tax, but not EV-associated Tax. Also, lower density EVs from HTLV-1-infected cells, separated by an Iodixanol density gradient, are positive for gp61+++/Tax+++/HBZ+ proteins (HTLV-1 EVs). We found that HTLV-1 EVs are not infectious when tested in multiple cell lines. However, these EVs promote cell-to-cell contact of uninfected cells, a phenotype which was enhanced with IR, potentially promoting viral spread. We treated humanized NOG mice with HTLV-1 EVs prior to infection and observed an increase in viral RNA synthesis in mice compared to control (EVs from uninfected cells). Proviral DNA levels were also quantified in blood, lung, spleen, liver, and brain post-treatment with HTLV-1 EVs, and we observed a consistent increase in viral DNA levels across all tissues, especially the brain. Finally, we show direct implications of EVs in viral spread and disease progression and suggest a two-step model of infection including the release of EVs from donor cells and recruitment of recipient cells as well as an increase in recipient cell-to-cell contact promoting viral spread.

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Section: Discussionsupporting

confidence: 91%

HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact

et al. 2019

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“…Additionally, the proinflammatory cytokines, IFN-γ and TNF-α, were detected in healthy PBMCs after exposure to EVs isolated from HTLV-1-infected cells. This finding indicates that EVs containing Tax mediate the release of these two cytokines and the activation of T helper 1 (Th1) immune response in the treated PBMCs [109]. This finding could explain the inflammation which is predominantly seen in HAM/TSP patients with Th1 phenotype [110].…”

Section: Ev Cargo In Viral Infectionmentioning

confidence: 85%

Extracellular Vesicles in HTLV-1 Communication: The Story of an Invisible Messenger

Sharif

Pinto

Mensah

et al. 2020

Viruses

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Human T-cell lymphotropic virus type 1 (HTLV-1) infects 5–10 million people worldwide and is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as other inflammatory diseases. A major concern is that the most majority of individuals with HTLV-1 are asymptomatic carriers and that there is limited global attention by health care officials, setting up potential conditions for increased viral spread. HTLV-1 transmission occurs primarily through sexual intercourse, blood transfusion, intravenous drug usage, and breast feeding. Currently, there is no cure for HTLV-1 infection and only limited treatment options exist, such as class I interferons (IFN) and Zidovudine (AZT), with poor prognosis. Recently, small membrane-bound structures, known as extracellular vesicles (EVs), have received increased attention due to their potential to carry viral cargo (RNA and proteins) in multiple pathogenic infections (i.e., human immunodeficiency virus type I (HIV-1), Zika virus, and HTLV-1). In the case of HTLV-1, EVs isolated from the peripheral blood and cerebral spinal fluid (CSF) of HAM/TSP patients contained the viral transactivator protein Tax. Additionally, EVs derived from HTLV-1-infected cells (HTLV-1 EVs) promote functional effects such as cell aggregation which enhance viral spread. In this review, we present current knowledge surrounding EVs and their potential role as immune-modulating agents in cancer and other infectious diseases such as HTLV-1 and HIV-1. We discuss various features of EVs that make them prime targets for possible vehicles of future diagnostics and therapies.

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Section: Exosomes and Other Enveloped Virusesmentioning

confidence: 99%

“…HTLV-1 is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma [63][64][65]. The transactivator protein Tax expressed by HTLV-1 affects many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, apoptosis, and proinflammatory cytokines [63,64]. Recent results showed that the exosomes derived from HTLV contain functional HTLV-1 proteins (such as Tax protein) and mRNAs (tax, HBZ, and Env mRNAs), which can be transferred to recipient cells by exosome and stimulate the production of proinflammatory cytokines, such as IFN-γ, IL-6, and TNF-α, and T helper (Th) 1 -immune response [63,64,66,67].…”

Section: Exosomes and Other Enveloped Virusesmentioning

confidence: 99%

“…The transactivator protein Tax expressed by HTLV-1 affects many critical cellular pathways, including host cell DNA damage response mechanisms, cell cycle progression, apoptosis, and proinflammatory cytokines [63,64]. Recent results showed that the exosomes derived from HTLV contain functional HTLV-1 proteins (such as Tax protein) and mRNAs (tax, HBZ, and Env mRNAs), which can be transferred to recipient cells by exosome and stimulate the production of proinflammatory cytokines, such as IFN-γ, IL-6, and TNF-α, and T helper (Th) 1 -immune response [63,64,66,67]. Furthermore, exosomes produced by DCs or macrophages contain MHC class I and II molecules, as well as T-cell co-stimulatory molecules, which act as important factors in antigen presentation during HTLV-1 infection [9].…”

Section: Exosomes and Other Enveloped Virusesmentioning

confidence: 99%

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Recent Progress on Exosomes in RNA Virus Infection

Zhang

Chen

et al. 2021

Viruses

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Recent research indicates that most tissue and cell types can secrete and release membrane-enclosed small vesicles, known as exosomes, whose content reflects the physiological/pathological state of the cells from which they originate. These exosomes participate in the communication and cell-to-cell transfer of biologically active proteins, lipids, and nucleic acids. Studies of RNA viruses have demonstrated that exosomes release regulatory factors from infected cells and deliver other functional host genetic elements to neighboring cells, and these functions are involved in the infection process and modulate the cellular responses. This review provides an overview of the biogenesis, composition, and some of the most striking functions of exosome secretion and identifies physiological/pathological areas in need of further research. While initial indications suggest that exosome-mediated pathways operate in vivo, the exosome mechanisms involved in the related effects still need to be clarified. The current review focuses on the role of exosomes in RNA virus infections, with an emphasis on the potential contributions of exosomes to pathogenesis.

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TAX-mRNA-Carrying Exosomes from Human T Cell Lymphotropic Virus Type 1-Infected Cells Can Induce Interferon-Gamma ProductionIn Vitro

Cited by 17 publications

References 34 publications

HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact

HTLV-1 Extracellular Vesicles Promote Cell-to-Cell Contact

Extracellular Vesicles in HTLV-1 Communication: The Story of an Invisible Messenger

Recent Progress on Exosomes in RNA Virus Infection

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