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Volume 105, Issue 3

Downregulation of endogenous nectin1 in human keratinocytes by herpes simplex virus 1 glycoprotein D excludes superinfection but does not affect NK cell function Open Access

Abstract

Many viruses downregulate their cognate receptors, facilitating virus replication and pathogenesis via processes that are not yet fully understood. In the case of herpes simplex virus 1 (HSV1), the receptor binding protein glycoprotein D (gD) has been implicated in downregulation of its receptor nectin1, but current understanding of the process is limited. Some studies suggest that gD on the incoming virion is sufficient to achieve nectin1 downregulation, but the virus-encoded E3 ubiquitin ligase ICP0 has also been implicated. Here we have used the physiologically relevant nTERT human keratinocyte cell type – which we have previously shown to express readily detectable levels of endogenous nectin1 – to conduct a detailed investigation of nectin1 expression during HSV1 infection. In these cells, nectin1, but not nectin2 or the transferrin receptor, disappeared from the cell surface in a process that required virus protein synthesis rather than incoming virus, but did not involve virus-induced host shutoff. Furthermore, gD was not only required but was sufficient for nectin1 depletion, indicating that no other virus proteins are essential. NK cells were shown to be activated in the presence of keratinocytes, a process that was greatly inhibited in cells infected with wild-type virus. However, degranulation of NK cells was also inhibited in ΔgD-infected cells, indicating that blocking of NK cell activation was independent of gD downregulation of nectin1. By contrast, a superinfection time-course revealed that the ability of HSV1 infection to block subsequent infection of a GFP-expressing HSV1 was dependent on gD and occurred in line with the timing of nectin1 downregulation. Thus, the role of gD-dependent nectin1 impairment during HSV infection is important for virus infection, but not immune evasion, which is achieved by other mechanisms.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): glycoprotein D , HSV1 , keratinocyte , nectin1 , NK cell ligand , superinfection exclusion and virus receptor
Funding
This study was supported by the:
  • Wellcome Trust (Award 221725/Z/20/Z)
    • Principle Award Recipient: EddieChung Yern Wang
  • Medical Research Council (Award MR/V000489/1)
    • Principle Award Recipient: EddieChung Yern Wang
  • Medical Research Council (Award MR/P001602/1)
    • Principle Award Recipient: EddieChung Yern Wang
  • British Skin Foundation (Award 035/s/17)
    • Principle Award Recipient: GillianElliott
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2024-03-12
2024-04-27
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Downregulation of endogenous nectin1 in human keratinocytes by herpes simplex virus 1 glycoprotein D excludes superinfection but does not affect NK cell function
J. Gen. Virol. 105, 001969 (2024); https://doi.org/10.1099/jgv.0.001969
/content/journal/jgv/10.1099/jgv.0.001969
/content/journal/jgv/10.1099/jgv.0.001969
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