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

Whitaker, Emily; Matheson, Nicholas J; Perlee, Sarah; Munson, Phillip; Symeonides, Menelaos; Thali, Markus

doi:10.3390/v11121082

Cited by 12 publications

(13 citation statements)

References 70 publications

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“…Tetraspanins constitute a large family of transmembrane proteins involved in the organization of specialized membrane microdomains through their ability to interact with numerous partners, including integrins, leukocyte receptors, cytoskeleton, and signaling proteins ( Hemler, 2005 ). Thus, tetraspanins participate in many biological processes, including cell fusion where they exert either inhibitory or activating effects depending on the experimental settings and the identity of the cell partners ( Gordon-Alonso et al, 2006 ; Weng et al, 2009 ; Whitaker et al, 2019 ). Upon the 18 tetraspanins expressed by monocytes and macrophages, CD9 and CD81 have been shown to be involved in cell migration and fusion ( Takeda et al, 2008 ; Takeda et al, 2003 ).…”

Section: Resultsmentioning

confidence: 99%

Productive HIV-1 infection of tissue macrophages by fusion with infected CD4+ T cells

Mascarau

Woottum

Fromont

et al. 2023

Journal of Cell Biology

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Macrophages are essential for HIV-1 pathogenesis and represent major viral reservoirs. Therefore, it is critical to understand macrophage infection, especially in tissue macrophages, which are widely infected in vivo, but poorly permissive to cell-free infection. Although cell-to-cell transmission of HIV-1 is a determinant mode of macrophage infection in vivo, how HIV-1 transfers toward macrophages remains elusive. Here, we demonstrate that fusion of infected CD4+ T lymphocytes with human macrophages leads to their efficient and productive infection. Importantly, several tissue macrophage populations undergo this heterotypic cell fusion, including synovial, placental, lung alveolar, and tonsil macrophages. We also find that this mode of infection is modulated by the macrophage polarization state. This fusion process engages a specific short-lived adhesion structure and is controlled by the CD81 tetraspanin, which activates RhoA/ROCK-dependent actomyosin contractility in macrophages. Our study provides important insights into the mechanisms underlying infection of tissue-resident macrophages, and establishment of persistent cellular reservoirs in patients.

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Section: Resultsmentioning

confidence: 99%

Productive HIV-1 infection of tissue macrophages by fusion with infected CD4+ T cells

Mascarau

Woottum

Fromont

et al. 2023

Journal of Cell Biology

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“…In this context, the antitumor effects observed with anti-CD81 mAbs 5A6 look promising. 5A6 proved to be safe in rodent models and it revealed marked anticancer activities in xenografted tumor models [ 88 , 115 ]. However, on the other side, a pleiotropic action may lead to more unwanted side effects and toxicities.…”

Section: Discussionmentioning

confidence: 99%

“…The CD81/EWI-2 interaction has multiple functions, notably acting as a linker of the tetraspanin web to the actin cytoskeleton [ 87 ], and this interaction plays roles in different pathologies. CD81/EWI-2 interaction is a regulatory factor for glioblastoma cell growth and motility [ 60 ], but also for HCV and HIV infection [ 61 , 88 ]. Notably, the HIV-1 virus uses CD81-lined vesicle structures to infect astrocytes, and then these energy-consuming glial cells support trans-infection of HIV-1 to T-cells [ 89 ].…”

Section: Cd81 Biology Trafficking and Signalingmentioning

confidence: 99%

Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

Bailly

Thuru

2023

Cancers

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Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also an anticancer target implicated in cancer cell proliferation and mobility, and in tumor metastasis. CD81 signaling contributes to the development of solid tumors (notably colorectal, liver and gastric cancers) and has been implicated in the aggressivity of B-cell lymphomas. A variety of protein partners can interact with CD81, either to regulate attachment and uptake of viruses (HCV E2, claudin-1, IFIM1) or to contribute to tumor growth and dissemination (CD19, CD44, EWI-2). CD81-protein interactions can be modulated with molecules targeting the extracellular domain of CD81, investigated as antiviral and/or anticancer agents. Several monoclonal antibodies anti-CD81 have been developed, notably mAb 5A6 active against invasion and metastasis of triple-negative breast cancer cells. CD81-EC2 can also be targeted with natural products (trachelogenin and harzianoic acids A-B) and synthetic compounds (such as benzothiazole-quinoline derivatives). They are weak CD81 binders but offer templates for the design of new compounds targeting the open EC2 loop. There is no anti-CD81 compound in clinical development at present, but this structurally well-characterized tetraspanin warrants more substantial considerations as a drug target.

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“…Moreover, calcineurin regulates cell fusion needed for bone formation in that its inhibition by tacrolimus reduces the formation of differentiated multinucleated osteoclasts [ 60 , 61 ]. While other cell factors contribute to controlling virally induced cell-cell fusion, for example, IFITM, tetraspanin, Ezrin, and EWI-2, which were shown to inhibit T cell syncytia induced by HIV [ 62 – 66 ], to our knowledge, calcineurin has not been reported to regulate cell fusion induced by any of the fusion inducing viruses. The finding that inhibition of calcineurin phosphatase activity also enhanced cell fusion induced by HSV-1 gB/gH-gL/gD highlights that calcineurin has a general role in viral fusion regulation.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin phosphatase activity regulates Varicella-Zoster Virus induced cell-cell fusion

et al. 2020

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Cell-cell fusion (abbreviated as cell fusion) is a characteristic pathology of medically important viruses, including varicella-zoster virus (VZV), the causative agent of chickenpox and shingles. Cell fusion is mediated by a complex of VZV glycoproteins, gB and gH-gL, and must be tightly regulated to enable skin pathogenesis based on studies with gB and gH hyperfusogenic VZV mutants. Although the function of gB and gH-gL in the regulation of cell fusion has been explored, whether host factors are directly involved in this regulation process is unknown. Here, we discovered host factors that modulated VZV gB/gH-gL mediated cell fusion via high-throughput screening of bioactive compounds with known cellular targets. Two structurally related non-antibiotic macrolides, tacrolimus and pimecrolimus, both significantly increased VZV gB/gH-gL mediated cell fusion. These compounds form a drug-protein complex with FKBP1A, which binds to calcineurin and specifically inhibits calcineurin phosphatase activity. Inhibition of calcineurin phosphatase activity also enhanced both herpes simplex virus-1 fusion complex and syncytin-1 mediated cell fusion, indicating a broad role of calcineurin in modulating this process. To characterize the role of calcineurin phosphatase activity in VZV gB/gH-gL mediated fusion, a series of biochemical, biological and infectivity assays was performed. Pimecrolimus-induced, enhanced cell fusion was significantly reduced by shRNA knockdown of FKBP1A, further supporting the role of calcineurin phosphatase activity in fusion regulation. Importantly, inhibition of calcineurin phosphatase activity during VZV infection caused exaggerated syncytia formation and suppressed virus propagation, which was consistent with the previously reported phenotypes of gB and gH hyperfusogenic VZV mutants. Seven host cell proteins that remained uniquely phosphorylated when calcineurin phosphatase activity was inhibited were identified as potential downstream factors involved in fusion regulation. These findings demonstrate that calcineurin is a critical host cell factor pivotal in the regulation of VZV induced cell fusion, which is essential for VZV pathogenesis.

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

Cited by 12 publications

References 70 publications

Productive HIV-1 infection of tissue macrophages by fusion with infected CD4+ T cells

Productive HIV-1 infection of tissue macrophages by fusion with infected CD4+ T cells

Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases

Calcineurin phosphatase activity regulates Varicella-Zoster Virus induced cell-cell fusion

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