title: Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus.
abstract: Off-target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99% in murine (J774A.1) macrophages and by 50% in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 min post virus administration. Circulating virus was still detectable 30 min post infusion in mice pre-dosed with poly(I) whereas no detectable MV was found at 5-10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors: Y-P
authors: YP
authors: Liu
authors: C
authors: C
authors: Tong
authors: A
authors: A
authors: Dispenzieri
authors: M J
authors: MJ
authors: Federspiel
authors: S J
authors: SJ
authors: Russell
authors: K-W
authors: KW
authors: Peng
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D008459:Measles virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000628:therapy* / Q000821:virology; D011069:Poly I / Q000494:pharmacology*; D013154:Spleen / Q000821:virology; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D011069:Poly I