title: Enforced covalent trimerisation of soluble feline CD134 (OX40)-ligand generates a functional antagonist of feline immunodeficiency virus.
abstract: The feline immunodeficiency virus (FIV) targets activated CD4-positive helper T cells preferentially, inducing an AIDS-like immunodeficiency in its natural host species, the domestic cat. The primary receptor for FIV is CD134, a member of the tumour necrosis factor receptor superfamily (TNFRSF) and all primary viral strains tested to date use CD134 for infection. To investigate the effect of the natural ligand for CD134 on FIV infection, feline CD134L was cloned and expressed in soluble forms. However, in contrast to murine or human CD134L, soluble feline CD134L (sCD134L) did not bind to CD134. Receptor-binding activity was restored by enforced covalent trimerisation following the introduction of a synthetic trimerisation domain from tenascin (TNC). Feline and human TNC-CD134Ls retained the species-specificity of the membrane-bound forms of the ligand while murine TNC-CD134L displayed promiscuous binding to feline, human or murine CD134. Feline and murine TNC-CD134Ls were antagonists of FIV infection; however, potency was both strain-specific and substrate-dependent, indicating that the modulatory effects of endogenous sCD134L, or exogenous CD134Lbased therapeutics, may vary depending on the viral strain.
authors.affiliation: Retrovirus Research Laboratory, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, United Kingdom. b.willett@vet.gla.ac.uk
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Willett
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: McMonagle
authors.forename: Nicola
authors.initials: N
authors.lastname: Logan
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Hosie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002415:Cats; D002460:Cell Line; D016181:Feline Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000276:immunology / Q000502:physiology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D053278:OX40 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055503:Protein Multimerization; D053262:Receptors, OX40 / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity; D019063:Tenascin / Q000235:genetics; D053586:Virus Internalization
chemical_list: D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D053278:OX40 Ligand; D053262:Receptors, OX40; D011993:Recombinant Fusion Proteins; D019063:Tenascin