Structural Basis For HIV-1 DNA Integration in the Human Genome

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA into the human genome is catalyzed by the viral integrase protein that requires the lens epithelium-derived growth factor (LEDGF), a cellular transcriptional coactivator. In the presence of LEDGF, integrase forms a stable complex in vitro and importantly becomes soluble by contrast with integrase alone which aggregates and precipitates. Using cryo-electron microscopy (EM) and single-particle reconstruction, we obtained three-dimensional structures of the wild type full length integrase-LEDGF complex with and without DNA. The stoichiometry of the complex was found to be (integrase)4-(LEDGF)2 and existing atomic structures were unambiguous positioned in the EM map. In vitro functional assays reveal that LEDGF increases integrase activity likely in maintaining a stable and functional integrase structure. Upon DNA binding, IN undergoes large conformational changes. Cryo-EM structure underlines the path of viral and target DNA and a model for DNA integration in human DNA is proposed.