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Journal of General Virology header logo Journal of General Virology

Volume 107, Issue 3

Knockout of key receptors (PDGFRA and NRP2) in the guinea pig model blocks direct and endocytic pathways of CMV cell entry Open Access

Abstract

The guinea pig with guinea pig cytomegalovirus (GPCMV) is the only small-animal model for congenital cytomegalovirus, a leading cause of cognitive impairment and hearing loss in newborns. GPCMV encodes human cytomegalovirus (HCMV) homologues of viral entry glycoprotein complexes, which are neutralizing-antibody vaccine targets. As with HCMV, GPCMV has two pathways of cell entry (direct and endocytic). Specific viral gH/gL-based complexes are necessary for receptor interaction and cell entry: gH/gL/gO trimer (direct) and pentamer complex (PC) (endocytic). Both pathways also require gB as the fusogenic protein. Direct GPCMV cell entry requires platelet-derived growth factor receptor alpha (PDGFRA), but an endocytic PC receptor remains unknown. We hypothesized that cellular knockout of direct and endocytic receptors would completely block infection, which cannot be achieved by gB-based antibodies. Candidate receptors including neuropilin proteins (NRP1, NRP2) and CD147 present on all established guinea pig cell lines were selected based on importance as common virus receptors or in fetal development. Results demonstrated that NRP2 interacted with PC, unlike NRP1 or CD147, in immunoprecipitation assays and eliminated NRP1/NRP2 heterodimer receptor interaction. The viral trimer only interacted with PDGFRA. Double knockout of PDGFRA/NRP2 completely blocked GPCMV infection. In contrast, the CD147/PDGFRA double knockout had limited GPCMV inhibition, and the single knockout of CD147 had no impact. Knockout of the various receptors had no effect on control HSV-1 infection. Ectopic expression of guinea pig cell receptors restored GPCMV infection but not human NRP2/PDGFRA, indicating a basis for the species-specific barrier for GPCMV and HCMV infection. Overall, results increase the translational relevance of GPCMV for the development of CMV intervention strategies.

  • Received:
  • Accepted:
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Keyword(s): cell receptors , congenital cytomegalovirus , cytomegalovirus , guinea pig , NRP2 and pentamer complex
Funding
This study was supported by the:
  • NHLBI Division of Intramural Research (Award R01AI100933)
    • Principal Award Recipient: AlistairMcGregor
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Award R01AI098984)
    • Principal Award Recipient: AlistairMcGregor
  • National Institute of Child Health and Human Development (Award R01HD090065)
    • Principal Award Recipient: AlistairMcGregor
© 2026 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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2026-03-10
2026-04-10

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Knockout of key receptors (PDGFRA and NRP2) in the guinea pig model blocks direct and endocytic pathways of CMV cell entry
J. Gen. Virol. 107, 002236 (2026); https://doi.org/10.1099/jgv.0.002236
/content/journal/jgv/10.1099/jgv.0.002236
/content/journal/jgv/10.1099/jgv.0.002236
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