Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection

Hung V. Trinh, Guillaume Lesage, Venus Chennamparampil, Benedikt Vollenweider, Christoph J. Burckhardt, Stefan Schauer, Menzo Havenga, Urs F. Greber, Silvio Hemmi

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The species B human adenoviruses (HAdVs) infect cells upon attaching to CD46 or desmoglein 2 (DSG-2) by one or several of their 12 fiber knob trimers (FKs). To test whether DSG-2 and CD46 simultaneously serve as virus receptors for adenovirus type 3 (Ad3), we performed individual and combined CD46/DSG-2 loss-of-function studies in human lung A549 and 16HBE14o cells. Our results suggest that in these cells, DSG-2 functions as a major attachment receptor for Ad3, whereas CD46 exerts a minor contribution to virus attachment and uptake in the range of ~10%. However, in other cells the role of CD46 may be more pronounced depending on, e.g., the expression levels of the receptors. To test if avidity allows Ad3/7 to use CD46 as a receptor, we performed gain-of-function studies. The cell surface levels of ectopically expressed CD46 in CHO or human M010119 melanoma cells lacking DSG-2 positively correlated with Ad3/7 infections, while Ad11/35 infections depended on CD46 but less on CD46 levels. Antibody-cross-linked soluble CD46 blocked Ad3/7/11/35 infections, while soluble CD46 alone blocked Ad11/35 but not Ad3/7. Soluble Ad3/7-FKs poorly inhibited Ad3/7 infection of CHO-CD46 cells, illustrating that Ad3/7-FKs bind with low affinity to CD46. This was confirmed by Biacore studies. Ad3/7-FK binding to immobilized CD46 at low density was not detected, unlike that of Ad11/35-FK. At higher CD46 densities, however, Ad3/7-FK bound to CD46 with only 15-fold-higher dissociation constants than those of Ad11/35-FK. These data show that an avidity mechanism for Ad3/7 binding to CD46 leads to infection of CD46-positive cells.

Original languageEnglish (US)
Pages (from-to)1623-1637
Number of pages15
JournalJournal of virology
Volume86
Issue number3
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Trinh, H. V., Lesage, G., Chennamparampil, V., Vollenweider, B., Burckhardt, C. J., Schauer, S., Havenga, M., Greber, U. F., & Hemmi, S. (2012). Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection. Journal of virology, 86(3), 1623-1637. https://doi.org/10.1128/JVI.06181-11