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Journal of Virology, June 2009, p. 6171-6183, Vol. 83, No. 12
0022-538X/09/$08.00+0 doi:10.1128/JVI.02163-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
The Virological Synapse Facilitates Herpes Simplex Virus Entry into T Cells
Martine Aubert,1
Miri Yoon,3
Derek D. Sloan,1,2
Patricia G. Spear,3 and
Keith R. Jerome1,2*
Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,1 Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195,2 Department of Microbiology-Immunology, Feinberg School of Medicine of Northwestern University, Chicago, Illinois 606113
Received 13 October 2008/ Accepted 20 March 2009
The virological synapse (VS) is a specialized molecular structure that facilitates the transfer of certain lymphotropic viruses into uninfected T cells. However, the role of the VS in the transfer of nonlymphotropic viruses into T cells is unknown. Herpes simplex virus (HSV) has been shown in vitro to infect T cells and modulate T-cell receptor function, thereby suppressing T-cell antiviral function. However, whether such infection of T cells occurs in vivo is unknown. Here, we examined whether T-cell infection could be observed in human HSV disease and investigated the mechanism of HSV entry into T cells. We found that HSV-infected T cells were readily detectable during human disease, suggesting that infection and modulation of T-cell function plays a role in human immunopathology. HSV infection of both CD4+ and CD8+ T cells occurred much more efficiently via direct cell-to-cell spread from infected fibroblasts than by cell-free virus. Activation of T cells increased their permissivity to HSV infection. Cell-to-cell spread to T cells did not require HSV glycoproteins E and I (gE and gI), which are critical for cell-to-cell spread between epithelial cells. Transfer of HSV to T cells required gD, and the four known entry receptors appear to be contributing to viral entry, with a dominant role for the herpesvirus entry mediator and nectin-1. VS-like structures enriched in activated lymphocyte function-associated antigen 1 (LFA-1) were observed at the point of contact between HSV-infected fibroblasts and T cells. Consistent with spread occurring via the VS, transfer of HSV was increased by activation of LFA-1, and cell-to-cell spread could be inhibited by antibodies to LFA-1 or gD. Taken together, these results constitute the first demonstration of VS-dependent cell-to-cell spread for a predominantly nonlymphotropic virus. Furthermore, they support an important role for infection and immunomodulation of T cells in clinical human disease. Targeting of the VS might allow selective immunopotentiation during infections with HSV or other nonlymphotropic viruses.
* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D3-100, Seattle, WA 98019. Phone: (206) 667-6793. Fax: (206) 667-4411. E-mail: kjerome{at}fhcrc.org
Published ahead of print on 1 April 2009.
Journal of Virology, June 2009, p. 6171-6183, Vol. 83, No. 12
0022-538X/09/$08.00+0 doi:10.1128/JVI.02163-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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