title: A mosaic fiber adenovirus serotype 5 vector containing reovirus sigma 1 and adenovirus serotype 3 knob fibers increases transduction in an ovarian cancer ex vivo system via a coxsackie and adenovirus receptor-independent pathway.
abstract: OBJECTIVE
  Adenovirus serotype 5 (Ad5) has been used for gene therapy with limited success due to insufficient infectivity in cells with low expression of the primary receptor, the coxsackie and adenovirus receptor (CAR). Evidence that adenovirus serotype receptors other than CAR may be of use was presented in previous studies that showed that the Ad3 receptor is expressed at high levels in ovarian cancer cells. We hypothesized that combined use of unique chimeric fibers in the context of novel mosaic adenovirus vectors would enhance infectivity via non-CAR pathways in ovarian cancer cells.
  
  
  METHODS
  We constructed and characterized Ad5 vectors that use Ad3 knob and reovirus fibers to generate a mosaic fiber virion. Serotype 3 Dearing reovirus uses a fiber-like sigma 1 protein to infect cells expressing sialic acid and junction adhesion molecule 1. We therefore constructed a mosaic fiber Ad5 vector, designated Ad5/3-sigma 1, encoding two fibers: a sigma 1 chimeric fiber and the chimeric Ad5/3 fiber composed of an Ad3 knob.
  
  
  RESULTS
  Functionally, Ad5/3-sigma 1 used sialic acid, junction adhesion molecule 1, and Ad3 receptor for cell transduction and achieved maximum infectivity enhancement in ovarian cancer cells with low CAR expression. Furthermore, Ad5/3-sigma 1 achieved infectivity enhancement in primary tissue slices of human ovarian tumor.
  
  
  CONCLUSIONS
  We have developed a new type of Ad5 vector with the novel tropism, possessing fibers from Ad3 and reovirus, which exhibits enhanced infectivity via CAR-independent pathway(s). In addition, the flexible genetic platform of vector allows different combination of fiber variants that can be incorporated within the same particle.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294-2172, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuruta
authors.forename: Larisa
authors.initials: L
authors.lastname: Pereboeva
authors.forename: Joel N
authors.initials: JN
authors.lastname: Glasgow
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Rein
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Rodney P
authors.initials: RP
authors.lastname: Rocconi
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D036022:Capsid Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019158:N-Acetylneuraminic Acid / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000628:therapy*; D011991:Receptors, Virus / Q000032:analysis / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods
chemical_list: C568771:CLMP protein, human; D036022:Capsid Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; C031728:sigma 1 protein, reovirus; D019158:N-Acetylneuraminic Acid