title: Epithelial stem cells as mucosal antigen-delivering cells: A novel AIDS vaccine approach.
abstract: A key obstacle limiting development of an effective AIDS vaccine is the inability to deliver antigen for a sufficient period of time resulting in weak and transient protection. HIV transmission occurs predominantly across mucosal surfaces; therefore, an ideal vaccine strategy would be to target HIV at mucosal entry sites to prevent infection. Such a novel strategy relies on the activation of mucosal immune response via presentation of viral antigens by the mucosal epithelial cells. The use of a terminally differentiated epithelial cell promoter to drive expression of antigens leading to viral protein production in the upper layers of the epithelium is central to the success of this approach. Our results show that when administered intradermally to mice, a GFP-reporter gene under the transcriptional control of the involucrin promoter is expressed in the upper layers of the epidermis and, although transduced cells were very low in number, high and sustained anti-GFP antibody production is observed in vivo. A subsequent experiment investigates the effectiveness of GFP-tagged replication-competent SIVdeltaNef and GFP-tagged replication-deficient SIVdeltaVifdeltaNef constructs under the transcriptional control of the involucrin promoter. Optimal conditions for production of pseudotyped VSV-G viral particles destined to transduce basal epithelial stem cells at the mucosal sites of entry of SIV in our animal model were determined. Altogether, the data demonstrate the feasibility of an epithelium-based vaccine containing involucrin-driven viral antigen encoding sequences that integrate into epithelial stem cells and show long-term expression in the upper layer of the epithelium even after multiple cycle of epithelia renewal. Such epithelium-based vaccine should elicit a long-term immunity against HIV/SIV infection at the site of entry of the virus.
authors.affiliation: Texas Biomedical Research Institute, Department of Virology and Immunology, San Antonio, TX 78227, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: White
authors.affiliation: Institut Pasteur, Unité de Rétrovirologie Moléculaire, CNRS URA 3015, 75724 Paris Cedex 15, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Chenciner
authors.affiliation: Texas Biomedical Research Institute, Department of Virology and Immunology, San Antonio, TX 78227, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Bonello
authors.affiliation: Texas Biomedical Research Institute, Department of Virology and Immunology, San Antonio, TX 78227, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Salas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, University of Nice-Sophia Antipolis, Valbonne, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Blancou
authors.affiliation: Texas Biomedical Research Institute, Department of Virology and Immunology, San Antonio, TX 78227, USA; Southwest National Primate Research Center, San Antonio, TX 78227, USA. Electronic address: mcgauduin@txbiomed.org.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gauduin
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000956:Antigens, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016503:Drug Delivery Systems; D015870:Gene Expression; D005822:Genetic Vectors; D007271:Injections, Intradermal; D051379:Mice; D013234:Stem Cells / Q000378:metabolism*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000956:Antigens, Viral; D014614:Vaccines, Synthetic
keywords: Antigen; Delivery; Epithelial stem cells; Mucosal; Simian immunodeficiency virus; Vaccine