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Open AccessArticle

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

1
University of Vermont, Department of Microbiology and Molecular Genetics, Burlington, 05405 VT, USA
2
University of Vermont, Graduate Program in Cellular, Molecular, and Biomedical Sciences, Burlington, 05405 VT, USA
3
Department of Medicine, University of Cambridge, CB2 0QQ Cambridge, UK
4
Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, CB2 0AW Cambridge, UK
5
University of Vermont, Department of Pathology and Laboratory Medicine, Burlington, 05405 VT, 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, 10065 NY, USA.
Current affiliation: Massachusetts General Hospital, Cutaneous Biology Research Center, Charlestown, 02129 MA, USA.
§
Co-senior authors.
Viruses 2019, 11(12), 1082; https://doi.org/10.3390/v11121082
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.
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
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.

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