The virological synapse facilitates herpes simplex virus entry into T cells
Open accessAbstract
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.
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Viruses have evolved several mechanisms, including cell-cell fusion, synapse formation, actin tails, filopodial bridges, and nanotubes, to facilitate secure and rapid cell-to-cell dissemination.
“Viruses have evolved several mechanisms, including cell-cell fusion, synapse formation, and induction of actin tails, filopodial bridges, or nanotubes, and are equipped with the necessary information to facilitate a secure and rapid cell-to-cell dissemination (Aubert et al., 2009; Bennett et al., 2009; Sherer et al., 2007; Sowinski et al., 2008).”
From Equid Herpesvirus-1 Exploits the Extracellular Matrix of Mononuclear Cells to Ensure Transport to Target Cells (2020) · cites this paper as Aubert et al., 2009
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Cell-to-cell transmission of viruses
Zhong, P., Agosto, L. M., Munro, J. B., & Mothes, W. (2013) · Current Opinion in Virology · doi:10.1016/j.coviro.2012.11.004 · Cited by 231 · see citing works
Kamel, M., Pavulraj, S., Fauler, B., Mielke, T., & Azab, W. (2020) · iScience · doi:10.1016/j.isci.2020.101615 · Cited by 7 · see citing works
“…fusion, synapse formation, and induction of actin tails, filopodial bridges, or nanotubes, and are equipped with the necessary information to facilitate a secure and rapid cell-to-cell dissemination (Aubert et al., 2009; Bennett et al., 2009; Sherer et al., 2007; Sowinski et al., 2008).”
- Authors
- Aubert, M., Yoon, M., Sloan, D. D., Spear, P. G., & Jerome, K. R.
- Affiliations
- Fred Hutch Cancer Center (US)
- Northwestern University (US)
- University of Washington (US)
- Corresponding author
- Jerome, Keith R.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2009-06-15
- Volume
- 83
- Issue
- 12
- Pages
- 6171-6183
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC2687377
- OpenAlex
- W2163367478
- Cited by
- 52
- References
- 64
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 1 · 2013: 1 · 2012: 5
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Washington
- National Institutes of Health
- National Cancer Institute (R01CA021776)
- National Institute of Allergy and Infectious Diseases (AI 36293, R37AI036293, R56AI065956)
- Topics
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- virological synapse, herpes simplex virus, T cell infection, cell-to-cell transmission, herpesvirus entry mediator, nectin-1, LFA-1, T cell activation
- MeSH terms
- Nectins, Animals, Chlorocebus aethiops, Fibroblasts, Herpes Simplex, Humans, Lymphocyte Activation, T-Lymphocytes, Vero Cells, Viral Envelope Proteins, Cell Adhesion Molecules, Herpesvirus 1, Human, Jurkat Cells, Mice, Receptors, Tumor Necrosis Factor, Member 14, Virus Internalization
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