title: Mouse Siglec-1 Mediates trans-Infection of Surface-bound Murine Leukemia Virus in a Sialic Acid N-Acyl Side Chain-dependent Manner.
abstract: Siglec-1 (sialoadhesin, CD169) is a surface receptor on human cells that mediates trans-enhancement of HIV-1 infection through recognition of sialic acid moieties in virus membrane gangliosides. Here, we demonstrate that mouse Siglec-1, expressed on the surface of primary macrophages in an interferon-α-responsive manner, captures murine leukemia virus (MLV) particles and mediates their transfer to proliferating lymphocytes. The MLV infection of primary B-cells was markedly more efficient than that of primary T-cells. The major structural protein of MLV particles, Gag, frequently co-localized with Siglec-1, and trans-infection, primarily of surface-bound MLV particles, efficiently occurred. To explore the role of sialic acid for MLV trans-infection at a submolecular level, we analyzed the potential of six sialic acid precursor analogs to modulate the sialylated ganglioside-dependent interaction of MLV particles with Siglec-1. Biosynthetically engineered sialic acids were detected in both the glycolipid and glycoprotein fractions of MLV producer cells. MLV released from cells carrying N-acyl-modified sialic acids displayed strikingly different capacities for Siglec-1-mediated capture and trans-infection; N-butanoyl, N-isobutanoyl, N-glycolyl, or N-pentanoyl side chain modifications resulted in up to 92 and 80% reduction of virus particle capture and trans-infection, respectively, whereas N-propanoyl or N-cyclopropylcarbamyl side chains had no effect. In agreement with these functional analyses, molecular modeling indicated reduced binding affinities for non-functional N-acyl modifications. Thus, Siglec-1 is a key receptor for macrophage/lymphocyte trans-infection of surface-bound virions, and the N-acyl side chain of sialic acid is a critical determinant for the Siglec-1/MLV interaction.
authors.affiliation: Institute of Medical Virology, National Reference Center for Retroviruses, University of Frankfurt, 60596 Frankfurt am Main, Germany,; Department of Infectious Diseases, Virology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Elina
authors.initials: E
authors.lastname: Erikson
authors.affiliation: the Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité Universitätsmedizin Berlin, 12200 Berlin, Germany.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Wratil
authors.affiliation: Biognos AB, 402 74 Göteborg, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Frank
authors.affiliation: Institute of Medical Virology, National Reference Center for Retroviruses, University of Frankfurt, 60596 Frankfurt am Main, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Ambiel
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, 20146 Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Pahnke
authors.affiliation: the AIDS Research Institute IrsiCaixa, Institut d'Investigatio en Ciencies de la Salut Germans Trias I Pujol, Universitat Autonoma de Barcelona, 08916 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Pino
authors.affiliation: the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Azadi
authors.affiliation: the AIDS Research Institute IrsiCaixa, Institut d'Investigatio en Ciencies de la Salut Germans Trias I Pujol, Universitat Autonoma de Barcelona, 08916 Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Izquierdo-Useros
authors.affiliation: the AIDS Research Institute IrsiCaixa, Institut d'Investigatio en Ciencies de la Salut Germans Trias I Pujol, Universitat Autonoma de Barcelona, 08916 Barcelona, Spain,; the Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, 20146 Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
authors.affiliation: Departments of Pharmacology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21218.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Schnaar
authors.affiliation: College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
authors.affiliation: the Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, Charité Universitätsmedizin Berlin, 12200 Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Reutter
authors.affiliation: Institute of Medical Virology, National Reference Center for Retroviruses, University of Frankfurt, 60596 Frankfurt am Main, Germany,; Department of Infectious Diseases, Virology, University of Heidelberg, 69120 Heidelberg, Germany,. Electronic address: oliver.keppler@kgu.de.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Keppler
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D005732:Gangliosides / Q000737:chemistry / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D007942:Leukemia, Experimental / Q000503:physiopathology / Q000821:virology; D008214:Lymphocytes / Q000502:physiology / Q000821:virology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D011991:Receptors, Virus / Q000737:chemistry / Q000502:physiology; D012192:Retroviridae Infections / Q000503:physiopathology / Q000821:virology; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D014412:Tumor Virus Infections / Q000503:physiopathology / Q000821:virology
chemical_list: D005732:Gangliosides; D016898:Interferon-alpha; D011991:Receptors, Virus; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D019158:N-Acetylneuraminic Acid
keywords: glycobiology; glycoconjugate; infectious disease; molecular modeling; retrovirus; sialic acid