Journal
MOLECULAR THERAPY
Volume 20, Issue 5, Pages 908-917Publisher
CELL PRESS
DOI: 10.1038/mt.2012.6
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Funding
- Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen)
- Ernst-Schering-Foundation
- amfAR
- KU Leuven Research Council [OT/09/047]
- Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) CellCoVir SBO [60813]
- Flanders Research Foundation (FWO) [G.0530.08]
- European Commission THINC [HEALTH-F3-2008-201032]
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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 CD4+ 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) Il2rgtm1Wjl/SzJ (NSG) mouse model. Threefold reduction in mean plasma viral load was obtained in mice engrafted with CD4+ 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 CD4+ cells were lost due to ongoing HIV replication. However, in mice transplanted with LEDGF(325-530) cells only a 20% decrease in CD4+ 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 CD4+ T-cells.
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