Integration is an essential step in the replication cycle of a retrovirus, such as the human immunodeficiency virus type 1 (HIV-1) (for a review,seeref. 1 ). After reverse transcription of the RNA genome, the DNA copy is transported into the nucleus and integrated in the host chromosome. The only viral enzyme required for HIV-1 integration is integrase (IN), a protein of 32 kDa encoded by the 3′-end of thepolgene. The enzyme is produced by protease-mediated cleavage of the gag-pol precursor during virion maturation. Integrase can be considered a site-specific endonuclease; the removal of two nucleotides creates a hydroxyl residue at each 3′-end of the viral DNA that will carry out a nucleophilic attack on the phosphodiester backbone of the host DNA.
