Next Article in Journal
Promises and Pitfalls of In Vivo Evolution to Improve Phage Therapy
Next Article in Special Issue
Real-Time Analysis of Individual Ebola Virus Glycoproteins Reveals Pre-Fusion, Entry-Relevant Conformational Dynamics
Previous Article in Journal
A Novel Benthic Phage Infecting Shewanella with Strong Replication Ability
Previous Article in Special Issue
Relating GPI-Anchored Ly6 Proteins uPAR and CD59 to Viral Infection
Open AccessArticle

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

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA
Graduate Program in Cellular, Molecular, and Biomedical Sciences, University of Vermont, Burlington, VT 05405, USA
Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge CB2 0AW, UK
Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT 05405, USA
Author to whom correspondence should be addressed.
Current affiliation: Memorial Sloan Kettering Cancer Center, Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, New York, NY 10065, USA.
Current affiliation: Massachusetts General Hospital, Cutaneous Biology Research Center, Charlestown, MA 02129, USA.
Co-senior authors.
Viruses 2019, 11(12), 1082;
Received: 14 October 2019 / Revised: 14 November 2019 / Accepted: 16 November 2019 / Published: 20 November 2019
(This article belongs to the Special Issue Mechanisms of Viral Fusion and Applications in Antivirals)
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. View Full-Text
Keywords: EWI-2; IGSF8; tetraspanin; HIV; cell–cell fusion; virological synapse; T cell; syncytia EWI-2; IGSF8; tetraspanin; HIV; cell–cell fusion; virological synapse; T cell; syncytia
Show Figures

Figure 1

MDPI and ACS Style

Whitaker, E.E.; Matheson, N.J.; Perlee, S.; Munson, P.B.; Symeonides, M.; Thali, M. EWI-2 Inhibits Cell–Cell Fusion at the HIV-1 Virological Presynapse. Viruses 2019, 11, 1082.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop