scholarly journals T Cell-Macrophage Fusion Triggers Multinucleated Giant Cell Formation for HIV-1 Spreading

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Lucie Bracq ◽  
Maorong Xie ◽  
Marie Lambelé ◽  
Lan-Trang Vu ◽  
Julie Matz ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Fusion ◽  
Giant Cells ◽  
Cell Transfer ◽  
Multinucleated Giant Cells ◽  
Virus Dissemination ◽  
Virus Spreading ◽  
Cell To Cell Transfer ◽  
Hiv 1 ◽  
Host Tissues

ABSTRACT HIV-1-infected macrophages participate in virus dissemination and establishment of virus reservoirs in host tissues, but the mechanisms for virus cell-to-cell transfer to macrophages remain unknown. Here, we reveal the mechanisms for cell-to-cell transfer from infected T cells to macrophages and virus spreading between macrophages. We show that contacts between infected T lymphocytes and macrophages lead to cell fusion for the fast and massive transfer of CCR5-tropic viruses to macrophages. Through the merge of viral material between T cells and macrophages, these newly formed lymphocyte-macrophage fused cells acquire the ability to fuse with neighboring noninfected macrophages. Together, these two-step envelope-dependent cell fusion processes lead to the formation of highly virus-productive multinucleated giant cells reminiscent of the infected multinucleated giant macrophages detected in HIV-1-infected patients and simian immunodeficiency virus-infected macaques. These mechanisms represent an original mode of virus transmission for viral spreading and a new model for the formation of macrophage virus reservoirs during infection. IMPORTANCE We reveal a very efficient mechanism involved in cell-to-cell transfer from infected T cells to macrophages and subsequent virus spreading between macrophages by a two-step cell fusion process. Infected T cells first establish contacts and fuse with macrophage targets. The newly formed lymphocyte-macrophage fused cells then acquire the ability to fuse with surrounding uninfected macrophages, leading to the formation of infected multinucleated giant cells that can survive for a long time, as evidenced in vivo in lymphoid organs and the central nervous system. This route of infection may be a major determinant for virus dissemination and the formation of macrophage virus reservoirs in host tissues during HIV-1 infection.

scholarly journals Cell-Cell Spread of Human Immunodeficiency Virus Type 1 Overcomes Tetherin/BST-2-Mediated Restriction in T cells

2010 ◽  
Vol 84 (23) ◽  
pp. 12185-12199 ◽  
Author(s):  
Clare Jolly ◽  
Nicola J. Booth ◽  
Stuart J. D. Neil
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Surface ◽  
Cell Transfer ◽  
Free Virion ◽  
Immunodeficiency Virus ◽  
Cell To Cell Transfer ◽  
Cell Spread ◽  
Hiv 1

ABSTRACT Direct cell-to-cell spread of human immunodeficiency virus type 1 (HIV-1) between T cells at the virological synapse (VS) is an efficient mechanism of viral dissemination. Tetherin (BST-2/CD317) is an interferon-induced, antiretroviral restriction factor that inhibits nascent cell-free particle release. The HIV-1 Vpu protein antagonizes tetherin activity; however, whether tetherin also restricts cell-cell spread is unclear. We performed quantitative cell-to-cell transfer analysis of wild-type (WT) or Vpu-defective HIV-1 in Jurkat and primary CD4+ T cells, both of which express endogenous levels of tetherin. We found that Vpu-defective HIV-1 appeared to disseminate more efficiently by cell-to-cell contact between Jurkat cells under conditions where tetherin restricted cell-free virion release. In T cells infected with Vpu-defective HIV-1, tetherin was enriched at the VS, and VS formation was increased compared to the WT, correlating with an accumulation of virus envelope proteins on the cell surface. Increasing tetherin expression with type I interferon had only minor effects on cell-to-cell transmission. Furthermore, small interfering RNA (siRNA)-mediated depletion of tetherin decreased VS formation and cell-to-cell transmission of both Vpu-defective and WT HIV-1. Taken together, these data demonstrate that tetherin does not restrict VS-mediated T cell-to-T cell transfer of Vpu-defective HIV-1 and suggest that under some circumstances tetherin might promote cell-to-cell transfer, either by mediating the accumulation of virions on the cell surface or by regulating integrity of the VS. If so, inhibition of tetherin activity by Vpu may balance requirements for efficient cell-free virion production and cell-to-cell transfer of HIV-1 in the face of antiviral immune responses.

scholarly journals HIV-1 Cell to Cell Transfer across an Env-induced, Actin-dependent Synapse

2004 ◽  
Vol 199 (2) ◽  
pp. 283-293 ◽  
Author(s):  
Clare Jolly ◽  
Kirk Kashefi ◽  
Michael Hollinshead ◽  
Quentin J. Sattentau
Keyword(s):  
T Cells ◽  
Target Cell ◽  
Lymphocyte Function ◽  
Cell Transfer ◽  
Chemokine Receptor Ccr5 ◽  
Surface Envelope ◽  
Direct Cell ◽  
Cell To Cell Transfer ◽  
Hiv 1 ◽  
Cell Cell

Direct cell–cell transfer is an efficient mechanism of viral dissemination within an infected host, and human immunodeficiency virus 1 (HIV-1) can exploit this mode of spread. Receptor recognition by HIV-1 occurs via interactions between the viral surface envelope glycoprotein (Env), gp120, and CD4 and a chemokine receptor, CCR5 or CXCR4. Here, we demonstrate that the binding of CXCR4-using HIV-1–infected effector T cells to primary CD4+/CXCR4+ target T cells results in rapid recruitment to the interface of CD4, CXCR4, talin, and lymphocyte function–associated antigen 1 on the target cell, and of Env and Gag on the effector cell. Recruitment of these membrane molecules into polarized clusters was dependent on Env engagement of CD4 and CXCR4 and required remodelling of the actin cytoskeleton. Transfer of Gag from effector to target cell was observed by 1 h after conjugate formation, was independent of cell–cell fusion, and was probably mediated by directed virion fusion with the target cell. We propose that receptor engagement by Env directs the rapid, actin-dependent recruitment of HIV receptors and adhesion molecules to the interface, resulting in a stable adhesive junction across which HIV infects the target cell.

scholarly journals Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Maorong Xie ◽  
Héloïse Leroy ◽  
Rémi Mascarau ◽  
Marie Woottum ◽  
Maeva Dupont ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Fusion ◽  
Myeloid Cells ◽  
Cell Spreading ◽  
Giant Cells ◽  
Target Cells ◽  
Multinucleated Giant Cells ◽  
Virus Transfer ◽  
Hiv 1

ABSTRACT Dendritic cells (DCs) and macrophages as well as osteoclasts (OCs) are emerging as target cells of HIV-1 involved in virus transmission, dissemination, and establishment of persistent tissue virus reservoirs. While these myeloid cells are poorly infected by cell-free viruses because of the high expression levels of cellular restriction factors such as SAMHD1, we show here that HIV-1 uses a specific and common cell-to-cell fusion mechanism for virus transfer and dissemination from infected T lymphocytes to the target cells of the myeloid lineage, including immature DCs (iDCs), OCs, and macrophages, but not monocytes and mature DCs. The establishment of contacts with infected T cells leads to heterotypic cell fusion for the fast and massive transfer of viral material into OC and iDC targets, which subsequently triggers homotypic fusion with noninfected neighboring OCs and iDCs for virus dissemination. These two cell-to-cell fusion processes are not restricted by SAMHD1 and allow very efficient spreading of virus in myeloid cells, resulting in the formation of highly virus-productive multinucleated giant cells. These results reveal the cellular mechanism for SAMHD1-independent cell-to-cell spreading of HIV-1 in myeloid cell targets through the formation of the infected multinucleated giant cells observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients. IMPORTANCE We demonstrate that HIV-1 uses a common two-step cell-to-cell fusion mechanism for massive virus transfer from infected T lymphocytes and dissemination to myeloid target cells, including dendritic cells and macrophages as well as osteoclasts. This cell-to-cell infection process bypasses the restriction imposed by the SAMHD1 host cell restriction factor for HIV-1 replication, leading to the formation of highly virus-productive multinucleated giant cells as observed in vivo in lymphoid and nonlymphoid tissues of HIV-1-infected patients. Since myeloid cells are emerging as important target cells of HIV-1, these results contribute to a better understanding of the role of these myeloid cells in pathogenesis, including cell-associated virus sexual transmission, cell-to-cell virus spreading, and establishment of long-lived viral tissue reservoirs.

Abstract 288: Distribution of Pathological Features and Inflammatory Cells in Patients With Giant Cell Myocarditis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
LIU SHANGYU ◽  
Yao Yan
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Giant Cells ◽  
Ventricular Septum ◽  
Free Wall ◽  
Pathological Features ◽  
Multinucleated Giant Cells ◽  
Giant Cell Myocarditis ◽  
Cardiac Lesions ◽  
The Right

Background: Giant-cell myocarditis (GCM) is a rare disease with a poor prognosis. The typical pathological features of GCM include an infiltration of multinucleated giant cells accompanied by numerous inflammatory immune cells. However, the etiology and pathophysiology of GCM remain largely unclear. Methods: Eight patients with pathological diagnoses with GCM underwent heart transplantation at our center. Hematoxylin- eosin (H-E) and Masson’s tri-chrome staining were performed on biopsies of the free walls of the right and left ventricles and interventricular septa of the original hearts to determine the characteristic distribution of cardiac lesions and the composition of infiltrating immune cells. A multiplex immunohistochemistry and multispectral imaging analysis were applied to further classify the specific types of inflammatory immune cells. Results: Inflammation found in a descending frequency gradually from the epicardium to the endocardium in the free wall of the left ventricle, but concentrated on the surface of right ventricular septum. Typical inflammatory infiltration and pathological changes were observed in the right-sided ventricular septum samples from all 8 patients. Numerous inflammatory immune cells, particularly CD4 + T cells, were detected in the lesion, which surrounded the emerging multinucleated giant cells. CD8 + T cells and a small number of regulatory T cells were scattered in the periphery. Conclusions: In GCM, cardiac lesions appear to concentrate particularly beneath the epicardium of the left ventricular free wall and the right side of the ventricular septum. These findings provide a rationale for the diagnostic use of conventional endocardial biopsy. The findings further suggest that myocardial injury is mediated by a variety of lymphocytes, especially CD4 + T cells.

scholarly journals Distinct efficacy of HIV-1 entry inhibitors to prevent cell-to-cell transfer of R5 and X4 viruses across a human placental trophoblast barrier in a reconstitution model in vitro

Retrovirology ◽  
2008 ◽  
Vol 5 (1) ◽  
pp. 31 ◽  
Author(s):  
Ahidjo Ayouba ◽  
Claude Cannou ◽  
Marie-Thérèse Nugeyre ◽  
Françoise Barré-Sinoussi ◽  
Elisabeth Menu
Keyword(s):  
Cell Transfer ◽  
Entry Inhibitors ◽  
Cell To Cell Transfer ◽  
Hiv 1

scholarly journals Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Maeva Dupont ◽  
Shanti Souriant ◽  
Luciana Balboa ◽  
Thien-Phong Vu Manh ◽  
Karine Pingris ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Risk Factor ◽  
Type I Interferon ◽  
Type I ◽  
Cell Transfer ◽  
Tunneling Nanotubes ◽  
Factors Associated ◽  
Tunneling Nanotube ◽  
Cell To Cell Transfer ◽  
Hiv 1

While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis (Mtb) worsens HIV-1 pathogenesis remain scarce. We showed that HIV-1 infection is exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic analysis in these macrophages, and revealed the up-regulation of Siglec-1 receptor. Siglec-1 expression depends on Mtb-induced production of type I interferon (IFN-I). In co-infected non-human primates, Siglec-1 is highly expressed by alveolar macrophages, whose abundance correlates with pathology and activation of IFN-I/STAT1 pathway. Siglec-1 localizes mainly on microtubule-containing TNT that are long and carry HIV-1 cargo. Siglec-1 depletion decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer, and abrogates the exacerbation of HIV-1 infection induced by Mtb. Altogether, we uncover a deleterious role for Siglec-1 in TB-HIV-1 co-infection and open new avenues to understand TNT biology.

scholarly journals Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Larisa Dubrovsky ◽  
Adam Ward ◽  
Soo-Ho Choi ◽  
Tatiana Pushkarsky ◽  
Beda Brichacek ◽  
...  
Keyword(s):  
T Cells ◽  
Lipid Rafts ◽  
Cell Fusion ◽  
Binding Protein ◽  
Rapid Progression ◽  
Inflammatory Factor ◽  
Hiv Disease ◽  
Hiv Replication ◽  
Apolipoprotein A ◽  
Hiv 1

ABSTRACT Apolipoprotein A-I binding protein (AIBP) is a protein involved in regulation of lipid rafts and cholesterol efflux. AIBP has been suggested to function as a protective factor under several sets of pathological conditions associated with increased abundance of lipid rafts, such as atherosclerosis and acute lung injury. Here, we show that exogenously added AIBP reduced the abundance of lipid rafts and inhibited HIV replication in vitro as well as in HIV-infected humanized mice, whereas knockdown of endogenous AIBP increased HIV replication. Endogenous AIBP was much more abundant in activated T cells than in monocyte-derived macrophages (MDMs), and exogenous AIBP was much less effective in T cells than in MDMs. AIBP inhibited virus-cell fusion, specifically targeting cells with lipid rafts mobilized by cell activation or Nef-containing exosomes. MDM-HIV fusion was sensitive to AIBP only in the presence of Nef provided by the virus or exosomes. Peripheral blood mononuclear cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, bound less AIBP than cells from donors with other HLA genotypes and were not protected by AIBP from rapid HIV-1 replication. These results provide the first evidence for the role of Nef exosomes in regulating HIV-cell fusion by modifying lipid rafts and suggest that AIBP is an innate factor that restricts HIV replication by targeting lipid rafts. IMPORTANCE Apolipoprotein A-I binding protein (AIBP) is a recently identified innate anti-inflammatory factor. Here, we show that AIBP inhibited HIV replication by targeting lipid rafts and reducing virus-cell fusion. Importantly, AIBP selectively reduced levels of rafts on cells stimulated by an inflammatory stimulus or treated with extracellular vesicles containing HIV-1 protein Nef without affecting rafts on nonactivated cells. Accordingly, fusion of monocyte-derived macrophages with HIV was sensitive to AIBP only in the presence of Nef. Silencing of endogenous AIBP significantly upregulated HIV-1 replication. Interestingly, HIV-1 replication in cells from donors with the HLA-B*35 genotype, associated with rapid progression of HIV disease, was not inhibited by AIBP. These results suggest that AIBP is an innate anti-HIV factor that targets virus-cell fusion.

scholarly journals Malignancy induced haemophagocytosis by erthroid cells and its transformation into a multinucleated giant cells – A unique clinical image

2021 ◽  
Vol 5 (1) ◽  
pp. 007-007
Keyword(s):  
T Cells ◽  
Giant Cells ◽  
Clinical Image ◽  
Cytokine Storm ◽  
Cytokine Release ◽  
Multinucleated Giant Cells

Haemophagocytosis is a dysregulated immune condition characterised by both inflammation and uncontrolled activation of macrophages and T-cells, which causes aberrant cytokine release, leading to cytokine storm [1] it can be primary or secondary, depending upon the etiology.

scholarly journals Adipoclast: a multinucleated fat-eating macrophage

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Antoni Olona ◽  
Subhankar Mukhopadhyay ◽  
Charlotte Hateley ◽  
Fernando O. Martinez ◽  
Siamon Gordon ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasma Membrane ◽  
Cell Membrane ◽  
Cell Fusion ◽  
Metabolic Activity ◽  
Current Knowledge ◽  
Giant Cells ◽  
Multinucleated Giant Cells ◽  
Review Current

AbstractCell membrane fusion and multinucleation in macrophages are associated with physiologic homeostasis as well as disease. Osteoclasts are multinucleated macrophages that resorb bone through increased metabolic activity resulting from cell fusion. Fusion of macrophages also generates multinucleated giant cells (MGCs) in white adipose tissue (WAT) of obese individuals. For years, our knowledge of MGCs in WAT has been limited to their description as part of crown-like structures (CLS) surrounding damaged adipocytes. However, recent evidence indicates that these cells can phagocytose oversized lipid remnants, suggesting that, as in osteoclasts, cell fusion and multinucleation are required for specialized catabolic functions. We thus reason that WAT MGCs can be viewed as functionally analogous to osteoclasts and refer to them in this article as adipoclasts. We first review current knowledge on adipoclasts and their described functions. In view of recent advances in single cell genomics, we describe WAT macrophages from a ‘fusion perspective’ and speculate on the ontogeny of adipoclasts. Specifically, we highlight the role of CD9 and TREM2, two plasma membrane markers of lipid-associated macrophages in WAT, which have been previously described as regulators of fusion and multinucleation in osteoclasts and MGCs. Finally, we consider whether strategies aiming to target WAT macrophages can be more selectively directed against adipoclasts.

scholarly journals EWI-2 Inhibits Cell–Cell Fusion at the HIV-1 Virological Presynapse

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1082
Author(s):  
Emily E. Whitaker ◽  
Nicholas J. Matheson ◽  
Sarah Perlee ◽  
Phillip B. Munson ◽  
Menelaos Symeonides ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Virological Synapse ◽  
Virus Particles ◽  
Fusion Inhibitors ◽  
Producer Cell ◽  
Cellular Components ◽  
Cell To Cell Transfer ◽  
Hiv 1 ◽  
Cell Cell

Cell-to-cell transfer of virus particles at the Env-dependent virological synapse (VS) is a highly efficient mode of HIV-1 transmission. While cell–cell fusion could be triggered at the VS, leading to the formation of syncytia and preventing exponential growth of the infected cell population, this is strongly inhibited by both viral (Gag) and host (ezrin and tetraspanins) proteins. Here, we identify EWI-2, a protein that was previously shown to associate with ezrin and tetraspanins, as a host factor that contributes to the inhibition of Env-mediated cell–cell fusion. Using quantitative fluorescence microscopy, shRNA knockdowns, and cell–cell fusion assays, we show that EWI-2 accumulates at the presynaptic terminal (i.e., the producer cell side of the VS), where it contributes to the fusion-preventing activities of the other viral and cellular components. We also find that EWI-2, like tetraspanins, is downregulated upon HIV-1 infection, most likely by Vpu. Despite the strong inhibition of fusion at the VS, T cell-based syncytia do form in vivo and in physiologically relevant culture systems, but they remain small. In regard to that, we demonstrate that EWI-2 and CD81 levels are restored on the surface of syncytia, where they (presumably) continue to act as fusion inhibitors. This study documents a new role for EWI-2 as an inhibitor of HIV-1-induced cell–cell fusion and provides novel insight into how syncytia are prevented from fusing indefinitely.

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