title: Lens epithelium-derived growth factor/p75 qualifies as a target for HIV gene therapy in the NSG mouse model.
abstract: Lens epithelium-derived growth factor (LEDGF/p75) is an essential cofactor of HIV integration. Both stable overexpression of the C-terminal part of LEDGF/p75 (LEDGF(325-530)) containing the integrase (IN)-binding domain (IBD) and stable knockdown (KD) of LEDGF/p75 are known to inhibit HIV infection in laboratory cell lines. Here, primary human CD(4)(+) T-cells were transduced with lentiviral vectors encoding LEDGF(325-530), the interaction-deficient mutant LEDGF(325-530)D366N, or a hairpin depleting LEDGF/p75 and challenged with HIV. Maximal protection of primary T-cells from HIV infection was obtained after LEDGF(325-530) overexpression reducing HIV replication 40-fold without evidence of cellular toxicity. This strategy was subsequently evaluated in the NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mouse model. Threefold reduction in mean plasma viral load was obtained in mice engrafted with CD(4)(+) T-cells expressing LEDGF(325-530) in comparison with engraftment with LEDGF(325-530)D366N cells. Four weeks after transplantation with LEDGF(325-530)D366N cells, 70% of the CD(4)(+) cells were lost due to ongoing HIV replication. However, in mice transplanted with LEDGF(325-530) cells only a 20% decrease in CD(4)(+) cells was measured. Liver and spleen sections of LEDGF(325-530) mice contained less HIV than LEDGF(325-530)D366N mice as measured by p24 antigen detection. LEDGF(325-530) overexpression potently inhibits HIV replication in vivo and protects against HIV mediated cell killing of primary CD(4)(+) T-cells.
authors.affiliation: Division of Molecular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Vets
authors.forename: Janine
authors.initials: J
authors.lastname: Kimpel
authors.forename: Andreas
authors.initials: A
authors.lastname: Volk
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Rik
authors.initials: R
authors.lastname: Schrijvers
authors.forename: Bert
authors.initials: B
authors.lastname: Verbinnen
authors.forename: Wim
authors.initials: W
authors.lastname: Maes
authors.forename: Dorothee
authors.initials: D
authors.lastname: Von Laer
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation / Q000821:virology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006678:HIV / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics / Q000628:therapy* / Q000821:virology; D006801:Humans; D007274:Injections, Intraperitoneal; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D016662:Virus Integration / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C119380:lens epithelium-derived growth factor