Due to the importance of human immunodeficiency virus type 1 (HIV-1)
integrase as a drug target, the biochemistry and structural aspects of retroviral
DNA integration have been the focus of intensive research during the past three decades. The retroviral
integrase enzyme acts on the linear double-stranded
viral DNA product of reverse transcription.
Integrase cleaves specific phosphodiester bonds near the
viral DNA ends during the 3' processing reaction. The
enzyme then uses the resulting
viral DNA 3'-OH groups during strand transfer to cut chromosomal target
DNA, which simultaneously joins both
viral DNA ends to target
DNA 5'-phosphates. Both reactions proceed via direct transesterification of scissile phosphodiester bonds by attacking nucleophiles: a water molecule for 3' processing, and the
viral DNA 3'-OH for strand transfer. X-ray crystal structures of prototype foamy virus
integrase-
DNA complexes revealed the architectures of the key
nucleoprotein complexes that form sequentially during the integration process and explained the roles of active site
metal ions in catalysis. X-ray crystallography furthermore elucidated the mechanism of action of
HIV-1 integrase strand transfer inhibitors, which are currently used to treat
AIDS patients, and provided valuable insights into the mechanisms of viral drug resistance.