title: EBV LMP1, a viral mimic of CD40, activates dendritic cells and functions as a molecular adjuvant when incorporated into an HIV vaccine.
abstract: HIV-1 does not significantly activate cellular immunity, which has made it difficult to use attenuated forms of HIV-1 as a vaccine. In contrast, EBV induces robust T cell responses in most infected individuals, perhaps as this virus contains LMP1, a viral mimic of CD40, which is a key activating molecule for DCs and macrophages. Consequently, studies were conducted using LMP1 and LMP1-CD40, a related construct formed by replacing the intracellular signaling domain of LMP1 with that of CD40. Upon electroporation into DCs, LMP1 and LMP1-CD40 mRNAs were sufficient to up-regulate costimulatory molecules and proinflammatory cytokines, indicating that these molecules can function in isolation as adjuvant-like molecules. As a first step toward an improved HIV vaccine, LMP1 and LMP1-CD40 were introduced into a HIV-1 construct to produce virions encoding these proteins. Transduction of DCs and macrophages with these viruses induced morphological changes and up-regulated costimulatory molecules and cytokine production by these cells. HIV-LMP1 enhanced the antigen-presenting function of DCs, as measured in an in vitro immunization assay. Taken together, these data show that LMP1 and LMP1-CD40 are portable gene cassettes with strong adjuvant properties that can be introduced into viruses such as HIV, which by themselves, are insufficient to induce protective cellular immunity.
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Gupta
authors.forename: James M
authors.initials: JM
authors.lastname: Termini
authors.forename: Liguo
authors.initials: L
authors.lastname: Niu
authors.forename: Saravana K
authors.initials: SK
authors.lastname: Kanagavelu
authors.forename: Helena
authors.initials: H
authors.lastname: Schmidtmayerova
authors.forename: Victoria
authors.initials: V
authors.lastname: Snarsky
authors.forename: Richard S
authors.initials: RS
authors.lastname: Kornbluth
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Stone
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D017951:Antigen Presentation; D019013:CD40 Antigens / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology*; D006678:HIV / Q000235:genetics / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry / Q000276:immunology; D014161:Transduction, Genetic; D014763:Viral Matrix Proteins / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins