title: Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro.
abstract: Eradication of human immunodeficiency virus-1 (HIV-1) from an infected individual requires a means of inducing production of virus from latently infected cells and stimulating an immune response against the infected cells. We report the development of lentiviral vectors that transduce dendritic cells (DCs) to both induce production of virus from latently infected cells and stimulate antigen-specific cytotoxic T lymphocytes (CTLs). The vectors package Vpx, a lentiviral accessory protein that counteracts the SAMHD1-mediated block to DC transduction, allowing for long-term expression of vector-encoded proteins. The vectors encode influenza or HIV-1-derived epitopes fused via a self-cleaving peptide to CD40L that releases the peptide into the endoplasmic reticulum for entry into the antigen presentation pathway. Expression of CD40L caused transduced DCs to mature and produce Th1-skewing cytokines. The DCs presented antigen to CD8 T cells, enhancing antigen-specific CTLs. Coculture of the transduced DCs with latently infected cells induced high-level virus production, an effect that was mediated by tumor necrosis factor alpha. The ability of a DC vaccine to reactivate latent HIV-1 and stimulate an adaptive immune response provide a means to reduce the size of the latent reservoir in patients. This strategy can also be applied to develop DC vaccines for other diseases.
authors.affiliation: 1] Department of Medicine, NYU School of Medicine, New York, NY, USA [2] Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Norton
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Miller
authors.affiliation: Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Bhardwaj
authors.affiliation: Department of Microbiology, NYU School of Medicine, New York, NY, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Landau
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005822:Genetic Vectors / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency
chemical_list: D016915:AIDS Vaccines; D019013:CD40 Antigens; D054334:Viral Regulatory and Accessory Proteins