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Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26).
- Source :
-
Journal of virology [J Virol] 2022 Feb 09; Vol. 96 (3), pp. e0082621. Date of Electronic Publication: 2021 Nov 17. - Publication Year :
- 2022
-
Abstract
- Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.
- Subjects :
- Adenoviruses, Human ultrastructure
Animals
Biomarkers
Blood Cell Count
CHO Cells
Cell Line
Coxsackie and Adenovirus Receptor-Like Membrane Protein chemistry
Cricetulus
Disease Models, Animal
Gene Expression
Humans
Membrane Cofactor Protein chemistry
Membrane Cofactor Protein genetics
Mice, Transgenic
Models, Biological
Models, Molecular
Mutagenesis
Protein Binding
Protein Conformation
Serogroup
Sialic Acids metabolism
Sialic Acids pharmacology
Structure-Activity Relationship
Adenovirus Infections, Human metabolism
Adenovirus Infections, Human virology
Adenoviruses, Human classification
Adenoviruses, Human physiology
Coxsackie and Adenovirus Receptor-Like Membrane Protein metabolism
Host-Pathogen Interactions
Membrane Cofactor Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 96
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 34787457
- Full Text :
- https://doi.org/10.1128/JVI.00826-21