HIV-1 integrase (IN; EC 2.7.7.49) is a polynucleotidyltransferase that catalyzes the integration of the DNA copy of the viral genome into the genome of the host cell. During viral infection, IN catalyzes two consecutive reactions, each proceeding by direct transesterification reactions catalyzed at a single active site in the enzyme's core. In the first reaction, IN removes two nucleotides from the from the 3′-end of each strand of the nascent viral DNA, leaving a recessed 3′CA dinucleotide. After migration into the nucleus of the infected cell as part of the nucleoprotein complex, IN covalently attaches each 3′ processed viral end to the host cell DNA, a reaction termed strand transfer[1]. IN also catalyzes an apparent reversal of the strand transfer reaction, a process known as disintegration[2].