Biodistribution of adeno-associated virus type 2 with mutations in the capsid that contribute to heparan sulfate proteoglycan binding
| Autor: | Irene Zolotukhin, Alfred S. Lewin, Nicholas Muzyczka, Kenneth H. Warrington, Marina S. Gorbatyuk, Oleg S. Gorbatyuk |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Cancer Research Mutant Biology Axonal Transport Sulfate binding Mice 03 medical and health sciences Transduction (genetics) Capsid Parvovirinae Virology Animals Adeno-Associated Virus Type 2 030304 developmental biology chemistry.chemical_classification 0303 health sciences 030306 microbiology Wild type Dependovirus Molecular biology Rats Amino acid Viral Tropism Phenotype Infectious Diseases chemistry Mutation Capsid Proteins Female Heparan Sulfate Proteoglycans Heparan sulfate proteoglycan binding Protein Binding |
| Zdroj: | Virus Research. 274:197771 |
| ISSN: | 0168-1702 |
| Popis: | We compared the phenotypes of three mutant AAV2 viruses containing mutations in arginine amino acids (R585, R588 and R484) previously shown to be involved in AAV2 heparan sulfate binding. The transduction efficiencies of wild type and mutant viruses were determined in the eye, the brain and peripheral organs following subretinal, striatal and intravenous injection, respectively, in mice and rats. We found that each of the three mutants (the single mutant R585A; the double mutant R585, 588A; and the triple mutant R585, 588, 484A) had a unique phenotype compared to wt and each other. R585A was completely defective for transducing peripheral organs via intravenous injection, suggesting that R585A may be useful for targeting peripheral organs by substitution of peptide ligands in the capsid surface. In the brain, all three mutants displayed widespread transduction, with the double mutant R585, 588A displaying the greatest spread and the greatest number of transduced neurons. The double mutant was also extremely efficient for retrograde transport, while the triple mutant was almost completely defective for retrograde transport. This suggested that R484 may be directly involved in interaction with the transport machinery. Finally, the double mutant also displayed improved transduction of the eye compared to wild type and the other mutants. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect