scholarly journals Extracellular vesicles from HTLV-1 infected cells modulate target cells and viral spread

Retrovirology ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Daniel O. Pinto ◽  
Sarah Al Sharif ◽  
Gifty Mensah ◽  
Maria Cowen ◽  
Pooja Khatkar ◽  
...  
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Spastic Paraparesis ◽  
Host Protein ◽  
Cell Contact ◽  
Target Cells ◽  
Viral Spread ◽  
Human T Cell ◽  
Cell Cell

Abstract Background The Human T-cell Lymphotropic Virus Type-1 (HTLV-1) is a blood-borne pathogen and etiological agent of Adult T-cell Leukemia/Lymphoma (ATLL) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1 has currently infected up to 10 million globally with highly endemic areas in Japan, Africa, the Caribbean and South America. We have previously shown that Extracellular Vesicles (EVs) enhance HTLV-1 transmission by promoting cell–cell contact. Results Here, we separated EVs into subpopulations using differential ultracentrifugation (DUC) at speeds of 2 k (2000×g), 10 k (10,000×g), and 100 k (100,000×g) from infected cell supernatants. Proteomic analysis revealed that EVs contain the highest viral/host protein abundance in the 2 k subpopulation (2 k > 10 k > 100 k). The 2 k and 10 k populations contained viral proteins (i.e., p19 and Tax), and autophagy proteins (i.e., LC3 and p62) suggesting presence of autophagosomes as well as core histones. Interestingly, the use of 2 k EVs in an angiogenesis assay (mesenchymal stem cells + endothelial cells) caused deterioration of vascular-like-tubules. Cells commonly associated with the neurovascular unit (i.e., astrocytes, neurons, and macrophages) in the blood–brain barrier (BBB) showed that HTLV-1 EVs may induce expression of cytokines involved in migration (i.e., IL-8; 100 k > 2 k > 10 k) from astrocytes and monocyte-derived macrophages (i.e., IL-8; 2 k > 10 k). Finally, we found that EVs were able to promote cell–cell contact and viral transmission in monocytic cell-derived dendritic cell. The EVs from both 2 k and 10 k increased HTLV-1 spread in a humanized mouse model, as evidenced by an increase in proviral DNA and RNA in the Blood, Lymph Node, and Spleen. Conclusions Altogether, these data suggest that various EV subpopulations induce cytokine expression, tissue damage, and viral spread.

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

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1422
Author(s):  
Sarah Al Sharif ◽  
Daniel O. Pinto ◽  
Gifty A. Mensah ◽  
Fatemeh Dehbandi ◽  
Pooja Khatkar ◽  
...  
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Virus Type ◽  
Current Knowledge ◽  
Spastic Paraparesis ◽  
Cell Aggregation ◽  
Type I ◽  
Viral Spread ◽  
Human T Cell ◽  
Hiv 1

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.

scholarly journals Candidate Polyanionic Microbicides Inhibit Human T-Cell Lymphotropic Virus Type 1 Receptor Interactions, Cell-Free Infection, and Cell-Cell Spread

2008 ◽  
Vol 53 (2) ◽  
pp. 678-687 ◽  
Author(s):  
Daniela Romer ◽  
David W. Brighty ◽  
Cynthia L. Robson ◽  
Quentin J. Sattentau
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Inflammatory Diseases ◽  
Sexual Transmission ◽  
Spastic Paraparesis ◽  
Virus Spread ◽  
Human T Cell ◽  
Cell Cell

ABSTRACT The human T-cell lymphotropic virus type 1 (HTLV-1) is the cause of adult T-cell leukemia and inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 can be transmitted through sexual contact, mother-to-child transmission, and exposure to contaminated blood. Microbicides are agents that interfere with microbial infectivity at mucous membranes, and candidates are under development for use against sexually transmitted viruses such as human immunodeficiency virus type 1. We previously demonstrated that cell surface polyanionic heparan sulfate proteoglycans bind the HTLV-1 envelope glycoprotein surface subunit gp46, facilitating cell-cell and cell-free virus spread in vitro. We now show, using assays for Env-receptor binding inhibition, Env-induced cell-cell fusion, cell-cell virus spread, and pseudotype HTLV-1 infectivity, that the soluble polyanions PRO 2000 and dextran sulfate are potent inhibitors of HTLV-1 spread in vitro, with PRO 2000 being the more promising candidate. The results of these studies suggest that candidate topical microbicides may be of use in reducing HTLV-1 sexual transmission.

scholarly journals Human T-cell leukaemia virus type 1: parasitism and pathogenesis

2017 ◽  
Vol 372 (1732) ◽  
pp. 20160272 ◽  
Author(s):  
Charles R. M. Bangham ◽  
Masao Matsuoka
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Inflammatory Diseases ◽  
Spastic Paraparesis ◽  
Cell Leukaemia ◽  
Cell Contact ◽  
Leukaemia Virus ◽  
Human T Cell ◽  
Infected Cells

Human T-cell leukaemia virus type 1 (HTLV-1) causes not only adult T-cell leukaemia-lymphoma (ATL), but also inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 transmits primarily through cell-to-cell contact, and generates abundant infected cells in the host in order to survive and transmit to a new host. The resulting high proviral load is closely associated with the development of ATL and inflammatory diseases. To increase the number of infected cells, HTLV-1 changes the immunophenotype of infected cells, induces proliferation and inhibits apoptosis through the cooperative actions of two viral genes, tax and HTLV-1 bZIP factor ( HBZ ). As a result, infected cells survive, proliferate and infiltrate into the tissues, which is critical for transmission of the virus. Thus, the strategy of this virus is indivisibly linked with its pathogenesis, providing a clue for prevention and treatment of HTLV-1-induced diseases. This article is part of the themed issue ‘Human oncogenic viruses’.

Use of conjugates made between a cytolytic T cell clone and target cells to study the redistribution of membrane molecules in cell contact areas

1990 ◽  
Vol 97 (2) ◽  
pp. 335-347
Author(s):  
P. Andre ◽  
A.M. Benoliel ◽  
C. Capo ◽  
C. Foa ◽  
M. Buferne ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Cell Interaction ◽  
Cell Contact ◽  
Computer Assisted ◽  
Target Cells ◽  
Contact Areas ◽  
Surface Molecules ◽  
T Cell Clone ◽  
Cell Cell

In many models of cell-cell adhesion, it was reported that some cell membrane molecules might be redistributed into contact areas. However, this phenomenon was not subjected to precise quantification. In the present work, fluorescence microscopy, immunolabelling and digital image processing were combined to analyse quantitatively the spatial organization of specific or nonspecific conjugates made with a cytolytic T (CTL) lymphocyte clone (BM3.3) and target cells (EL4 or RDM4). Binding was achieved under calcium-free conditions to study the earliest steps of cell interaction, preceding CTL activation. Fluorescent antibodies were used to label class I histocompatibility molecules on both killer and target cells, and T cell receptor, CD3, CD8 and LFA-1 (CD18/CD11a) on the killer cells. Membrane bilayers were stained with a fluorescent phospholipid, glycoconjugates were labelled with periodic oxidation and Lucifer Yellow uptake, and polymerized actin was revealed with a fluorescent phallacidin derivative. Also, the fine geometry of killer-target interaction area was studied with electron microscopy and computer-assisted contour analysis. It is concluded that: (1) qualitative examination of fluorescence photomicrographs cannot permit accurate comparison between different fluorescence densities. (2) The cell-cell contact area was about fourfold higher in specific conjugates than in non-specific ones. (3) The surface density of adhesion molecules exhibited similar increases (between 30 and 80%) in the contact areas of both specific and nonspecific conjugates. (4) However, the amount of redistributed surface molecules was higher when cell-cell interaction was enhanced either by specific immunological recognition (in specific conjugates) or periodate oxidation. (5) Since redistribution did not require extracellular calcium and it was detected on nonspecific conjugates, this did not require full lymphocyte activation. Spatial reorganization of cell surface molecules may thus be a general consequence of adhesion, cell surface mobility and intermolecular forces.

scholarly journals Contact-Induced Mitochondrial Polarization Supports HIV-1 Virological Synapse Formation

2014 ◽  
Vol 89 (1) ◽  
pp. 14-24 ◽  
Author(s):  
Elisabetta Groppelli ◽  
Shimona Starling ◽  
Clare Jolly
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Virological Synapse ◽  
Cell Contact ◽  
Target Cells ◽  
Cell Contacts ◽  
Cell Spread ◽  
Hiv 1 ◽  
Cell Cell

ABSTRACTRapid HIV-1 spread between CD4 T lymphocytes occurs at retrovirus-induced immune cell contacts called virological synapses (VS). VS are associated with striking T cell polarization and localized virus budding at the site of contact that facilitates cell-cell spread. In addition to this, spatial clustering of organelles, including mitochondria, to the contact zone has been previously shown. However, whether cell-cell contact specifically induces dynamic T cell remodeling during VS formation and what regulates this process remain unclear. Here, we report that contact between an HIV-1-infected T cell and an uninfected target T cell specifically triggers polarization of mitochondria concomitant with recruitment of the major HIV-1 structural protein Gag to the site of cell-cell contact. Using fixed and live-cell imaging, we show that mitochondrial and Gag polarization in HIV-1-infected T cells occurs within minutes of contact with target T cells, requires the formation of stable cell-cell contacts, and is an active, calcium-dependent process. We also find that perturbation of mitochondrial polarization impairs cell-cell spread of HIV-1 at the VS. Taken together, these data suggest that HIV-1-infected T cells are able to sense and respond to contact with susceptible target cells and undergo dynamic cytoplasmic remodeling to create a synaptic environment that supports efficient HIV-1 VS formation between CD4 T lymphocytes.IMPORTANCEHIV-1 remains one of the major global health challenges of modern times. The capacity of HIV-1 to cause disease depends on the virus's ability to spread between immune cells, most notably CD4 T lymphocytes. Cell-cell transmission is the most efficient way of HIV-1 spread and occurs at the virological synapse (VS). The VS forms at the site of contact between an infected cell and an uninfected cell and is characterized by polarized assembly and budding of virions and clustering of cellular organelles, including mitochondria. Here, we show that cell-cell contact induces rapid recruitment of mitochondria to the contact site and that this supports efficient VS formation and consequently cell-cell spread. Additionally, we observed that cell-cell contact induces a mitochondrion-dependent increase in intracellular calcium, indicative of cellular signaling. Taken together, our data suggest that VS formation is a regulated process and thus a potential target to block HIV-1 cell-cell spread.

scholarly journals HIV Infection Stabilizes Macrophage-T Cell Interactions To Promote Cell-Cell HIV Spread

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Paul Lopez ◽  
Wan Hon Koh ◽  
Ryan Hnatiuk ◽  
Thomas T. Murooka
Keyword(s):  
T Cells ◽  
T Cell ◽  
Live Cell Imaging ◽  
Cell Contact ◽  
Cell Infection ◽  
Cell Contacts ◽  
3 Dimensional ◽  
Viral Spread ◽  
Large Numbers ◽  
Cell Cell

ABSTRACTMacrophages are susceptible to HIV infection and play an important role in viral dissemination through cell-cell contacts with T cells. However, our current understanding of macrophage-to-T cell HIV transmission is derived from studies that do not consider the robust migration and cell-cell interaction dynamics between these cells. Here, we performed live-cell imaging studies in 3-dimensional (3D) collagen that allowed CD4+T cells to migrate and to locate and engage HIV-infected macrophages, modeling the dynamic aspects of thein situenvironment in which these contacts frequently occur. We show that HIV+macrophages form stable contacts with CD4+T cells that are facilitated by both gp120-CD4 and LFA-1–ICAM-1 interactions and that prolonged contacts are a prerequisite for efficient viral spread. LFA-1–ICAM-1 adhesive contacts function to restrain highly motile T cells, since their blockade substantially destabilized macrophage-T cell contacts, resulting in abnormal tethering events that reduced cell-cell viral spread. HIV-infected macrophages displayed strikingly elongated podosomal extensions that were dependent on Nef expression but were dispensable for stable cell-cell contact formation. Finally, we observed persistent T cell infection in dynamic monocyte-derived macrophage (MDM)-T cell cocultures in the presence of single high antiretroviral drug concentrations but achieved complete inhibition with combination therapy. Together, our data implicate macrophages as drivers of T cell infection by altering physiological MDM-T cell contact dynamics to access and restrain large numbers of susceptible, motile T cells within lymphoid tissues.IMPORTANCEOnce HIV enters the lymphoid organs, exponential viral replication in T cells ensues. Given the densely packed nature of these tissues, where infected and uninfected cells are in nearly constant contact with one another, efficient HIV spread is thought to occur through cell-cell contactsin vivo. However, this has not been formally demonstrated. In this study, we performed live-cell imaging studies within a 3-dimensional space to recapitulate the dynamic aspects of the lymphoid microenvironment and asked whether HIV can alter the morphology, migration capacity, and cell-cell contact behaviors between macrophages and T cells. We show that HIV-infected macrophages can engage T cells in stable contacts through binding of virus- and host-derived adhesive molecules and that stable macrophage-T cell contacts were required for high viral spread. Thus, HIV alters physiological macrophage-T cell interactions in order to access and restrain large numbers of susceptible, motile T cells, thereby playing an important role in HIV progression.

scholarly journals HIV-Captured DCs Regulate T Cell Migration and Cell-Cell Contact Dynamics to Enhance Viral Spread

iScience ◽  
2020 ◽  
Vol 23 (8) ◽  
pp. 101427 ◽  
Author(s):  
Wan Hon Koh ◽  
Paul Lopez ◽  
Oluwaseun Ajibola ◽  
Roshan Parvarchian ◽  
Umar Mohammad ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Contact Dynamics ◽  
Cell Contact ◽  
Viral Spread ◽  
T Cell Migration ◽  
Cell Cell

HIV-Bearing DCs Regulate T Cell Migration and Cell-Cell Contact Dynamics to Enhance Viral Spread

2020 ◽  
Author(s):  
Wan Hon Koh ◽  
Paul Lopez ◽  
Oluwaseun Ajibola ◽  
Roshan Parvarchian ◽  
Umar Mohammad ◽  
...  
Keyword(s):  
Cell Migration ◽  
T Cell ◽  
Contact Dynamics ◽  
Cell Contact ◽  
Viral Spread ◽  
T Cell Migration ◽  
Cell Cell

scholarly journals Shaping of T Cell Functions by Trogocytosis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1155
Author(s):  
Masafumi Nakayama ◽  
Arisa Hori ◽  
Saori Toyoura ◽  
Shin-Ichiro Yamaguchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Antigen Processing ◽  
Cell Contact ◽  
Target Cells ◽  
Dependent Manner ◽  
Mhc Molecules ◽  
Cell Functions ◽  
Cell Cell

Trogocytosis is an active process whereby plasma membrane proteins are transferred from one cell to the other cell in a cell-cell contact-dependent manner. Since the discovery of the intercellular transfer of major histocompatibility complex (MHC) molecules in the 1970s, trogocytosis of MHC molecules between various immune cells has been frequently observed. For instance, antigen-presenting cells (APCs) acquire MHC class I (MHCI) from allografts, tumors, and virally infected cells, and these APCs are subsequently able to prime CD8+ T cells without antigen processing via the preformed antigen-MHCI complexes, in a process called cross-dressing. T cells also acquire MHC molecules from APCs or other target cells via the immunological synapse formed at the cell-cell contact area, and this phenomenon impacts T cell activation. Compared with naïve and effector T cells, T regulatory cells have increased trogocytosis activity in order to remove MHC class II and costimulatory molecules from APCs, resulting in the induction of tolerance. Accumulating evidence suggests that trogocytosis shapes T cell functions in cancer, transplantation, and during microbial infections. In this review, we focus on T cell trogocytosis and the related inflammatory diseases.

scholarly journals Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Marcia Bellon ◽  
Izabela Bialuk ◽  
Veronica Galli ◽  
Xue-Tao Bai ◽  
Lourdes Farre ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Spastic Paraparesis ◽  
Cellular Transformation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Fragile Histidine Triad ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

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