title: Influence of chimeric human-bovine fibers on adenoviral uptake by liver cells and the antiviral immune response.
abstract: Human adenoviruses (HAdV) are widely used for in vitro and in vivo gene transfer. Viral hepatotropism, inflammatory responses and neutralization by pre-existing antibodies (NAbs) are obstacles for clinical applications of HAdV vectors. Although the multifactorial events leading to innate HAdV toxicity are far from being elucidated, there is a consensus that the majority of intravenously injected-HAdV vectors is sequestered by Kuppfer cells, probably independently of coagulation factors. In this study, we show that the adenoviral-associated humoral and innate cytokine immune responses are significantly reduced when HAdV-5 vector carrying human bovine chimeric fibers (HAdV-5-F2/BAdV-4) is intravenously injected into mice. Fiber pseudotyping modified its interaction with blood coagulation factors, as FIX and FX no longer mediate the infection of liver cells by HAdV-5-F2/BAdV-4. As a consequence, at early time points post-infection, several cytokines and chemokines (IFN-gamma, IL-6, IP-10, MCP-1, RANTES and MP1beta) were found to be present at lower levels in the plasma of mice that had been intravenously injected with HAdV-5-F2/BAdV-4 compared with mice injected with the parental vector HAdV-5. Moreover, genetic modification of the fiber allowed HAdV-5-F2/BAdV-4 to partially escape neutralization by NAbs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U837, Place de Verdun, Lille, France.
authors.forename: S
authors.initials: S
authors.lastname: Rogée
authors.forename: E
authors.initials: E
authors.lastname: Grellier
authors.forename: C
authors.initials: C
authors.lastname: Bernard
authors.forename: N
authors.initials: N
authors.lastname: Jouy
authors.forename: A
authors.initials: A
authors.lastname: Loyens
authors.forename: J C
authors.initials: JC
authors.lastname: Beauvillain
authors.forename: P
authors.initials: P
authors.lastname: Fender
authors.forename: S
authors.initials: S
authors.lastname: Corjon
authors.forename: S S
authors.initials: SS
authors.lastname: Hong
authors.forename: P
authors.initials: P
authors.lastname: Boulanger
authors.forename: B
authors.initials: B
authors.lastname: Quesnel
authors.forename: J C
authors.initials: JC
authors.lastname: D'Halluin
authors.forename: M
authors.initials: M
authors.lastname: Colin
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral; D001779:Blood Coagulation Factors / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D018925:Chemokines / Q000032:analysis; D002678:Chimera; D016207:Cytokines / Q000032:analysis; D005822:Genetic Vectors; D016679:Genome, Viral; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000821:virology; D051379:Mice; D014161:Transduction, Genetic
chemical_list: D000914:Antibodies, Viral; D001779:Blood Coagulation Factors; D018925:Chemokines; D016207:Cytokines