Fiber-mosaic adenovirus as a novel approach to design genetically modified adenoviral vectors.
Genetic modification of the adenovirus (Ad) capsid is one of the successful strategies to achieve viral retargeting. However, it has been widely recognized that structural constraints imposed by viral proteins limit the number and nature of incorporated targeting ligands and often hamper viral propagation. To address this issue, we propose a genetic fiber-mosaic virus (having two distinct fibers in one viral particle) as a means to facilitate fiber modifications. Fiber-mosaic virus having tandem fibers: a wild type (wt) fiber and second adjunctive fiber, will utilize natural viral entry for the conventional propagation of the vectors whereas, adjunctive fiber will serve multiple potential purposes such as targeting, purification, or imaging of viral particles via genetic incorporation of the corresponding functional moieties. We generated the mosaic adenovirus vector encoding two fibers: wild-type and adjunctive fiber--Fiber-Fibritin (FF) and confirmed incorporation of FF in the mosaic viral particles. We investigated binding specificity of the mosaic virus and the possible interference of the two fibers during virus life cycle. Fiber-mosaic Ad attained new binding properties provided by the second fiber, while preserving the binding ability attributed to the wt fiber. Our results suggest that the two fibers being presented and structurally separated on the viral particle may also function separately as binding counterparts for virus attachment. Therefore, the mosaic setting will allow more flexibility in Ad retargeting approaches.
Pereboeva
Larisa
L
Division of Human Gene Therapy, Department of Medicine, The Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Al 35294, USA.
Komarova
Svetlana
S
Mahasreshti
Parameshwar J
PJ
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D018390:Gene Targeting; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011991:Receptors, Virus / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014771:Virion / Q000737:chemistry; D019065:Virus Assembly; D014779:Virus Replication
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D036022:Capsid Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D011994:Recombinant Proteins; D014764:Viral Proteins; C057839:fibritin protein, Enterobacteria phage T4; C018315:hexon capsid protein, Adenovirus